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Steroid Hormone Signalling

Steroid Hormone Signalling


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Can the lipid-soluble hormones (like steroid hormones) go inside every cell, as their particular receptors are located in the cytoplasm or nucleus of the target cells? Is there anything special on the membrane of the target cells which enables the steroid hormone to know that it has to enter that particular type of cells and avoid others?

(Peptide hormones function through cognate receptors located on the cell membrane of the target cell.)


Note: Since my area of expertise is with peptide hormones, I will offer a partial answer.

Steroid hormones are carried through the circulation by binding to globular proteins. When these hormones are released from binding proteins, the classical route of action is by free diffusion through the cell membrane. This diffusion is due to their aromatic structure. You rightly point out that the classical receptors of these hormones are found in the cytoplasm or nucleus. For example, estrogen signalling as a classic signalling template which has genomic (DNA) and non-genomic (protein) targets to exert its effects.

Non-canonical signalling can occur through at least one G-protein coupled receptor (GPCR). Unlike most GPCR's which are localized to the cell membrane, GPR30 appears to be localized to the endoplasmic reticulum, which means steroid signalling still occurs through canonical means and also this newer pathway.

Then again, there are also steroid effects that modulate ion channels, for example GABA receptors. These are not specific receptors where only a steroid hormone can have an effect, yet they can activate or inhibit the effects (along with other drugs).


Hormonal Signaling in Biology and Medicine

Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology covers the endocrine secretions produced by every organ. This extensive collection of knowledge is organized by tissue, addressing how certain hormones are synthesized in multiple tissues, along with their structure, function and pathways, which are very applicable for researchers in drug design who need to focus on a specific step along the pathway. This is a must have reference for researchers in endocrinology and practicing endocrinologists, but it is also ideal for biochemists, pharmacologists, biologists and students.

Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology covers the endocrine secretions produced by every organ. This extensive collection of knowledge is organized by tissue, addressing how certain hormones are synthesized in multiple tissues, along with their structure, function and pathways, which are very applicable for researchers in drug design who need to focus on a specific step along the pathway. This is a must have reference for researchers in endocrinology and practicing endocrinologists, but it is also ideal for biochemists, pharmacologists, biologists and students.


Steroid Hormone Signalling - Biology

If one takes a closer look at the life cycle of the fruit fly, one quickly realizes that its growth is restricted to the three larval stages and that maturation occurs during metamorphosis. This temporal separation raises a central question: how does a larva decide that it has grown enough and that it is time to move on to maturation? What are the genes and hormones involved in this decision? Part of the answer can be found by examining pulses of the steroid hormone ecdysone, which trigger each of the major developmental transitions, including the two molts and puparium formation (see the figure). During metamorphosis the entire organism is remodeled until a sexually mature fly ecloses. Importantly, the energy required for metamorphosis has to be stored during larval stages, which is why larvae have to grow beyond a certain threshold weight to sustain this process. This threshold weight is the so-called critical weight. Roughly a day after this checkpoint is fulfilled, a small pulse of ecdysone will trigger the termination of feeding and the start of wandering behavior, which will eventually result in a late larval ecdysone peak and the onset of metamorphosis.

How does a larva measure its own weight? This question is far from trivial and still not well understood. We have identified a mutation in a nuclear receptor gene called DHR4 , which appears to be responsible for disrupting the animals’ ability to pupariate at the correct body size and weight. In addition, a disruption of DHR4 function can result in the premature onset of wandering behaviour as well as puparium formation, indicating that this nuclear receptor is critical for developmental timing as well.

DHR4 acts directly downstream of the receptor for ecdysone, which is called - not too surprisingly - the Ecdysone Receptor (short: EcR), which is also a nuclear receptor. However, we are more interested in the role of DHR4 in pathways that control critical weight. We are currently examining phenotypes associated with tissue-specific disruption and overexpression of this receptor, and are employing genomic strategies to determine which processes are regulated by this nuclear receptor.

The life cycle of a fly in the context of changing steroid hormone titer (here ecdysone, a so-called ecdysteroid). The fruit fly develops through three larval stages before it reaches puparium formation. The larval stages are separated by molts, which are controlled by pulses of ecdysone. Other major development events, such as hatching and the transition from a larva to a pupa, are also controlled by this hormone.


Contents

In many small organisms such as bacteria, quorum sensing enables individuals to begin an activity only when the population is sufficiently large. This signaling between cells was first observed in the marine bacterium Aliivibrio fischeri, which produces light when the population is dense enough. [10] The mechanism involves the production and detection of a signaling molecule, and the regulation of gene transcription in response. Quorum sensing operates in both gram-positive and gram-negative bacteria, and both within and between species. [11]

In slime moulds, individual cells known as amoebae aggregate together to form fruiting bodies and eventually spores, under the influence of a chemical signal, originally named acrasin. The individuals move by chemotaxis, i.e. they are attracted by the chemical gradient. Some species use cyclic AMP as the signal others such as Polysphondylium violaceum use other molecules, in its case N-propionyl-gamma-L-glutamyl-L-ornithine-delta-lactam ethyl ester, nicknamed glorin. [12]

In plants and animals, signaling between cells occurs either through release into the extracellular space, divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling (e.g., notch signaling). [13] Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. [14] Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells.

Synthesis and release Edit

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, Vasopressin, Acetylcholine), while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic acid), but important exceptions to both are numerous, and a same molecule can act both via surface receptors or in an intracrine manner to different effects. [14] In animal cells, specialized cells release these hormones and send them through the circulatory system to other parts of the body. They then reach target cells, which can recognize and respond to the hormones and produce a result. This is also known as endocrine signaling. Plant growth regulators, or plant hormones, move through cells or by diffusing through the air as a gas to reach their targets. [15] Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon monoxide. [16]

Exocytosis Edit

Exocytosis is the process by which a cell transports molecules such as neurotransmitters and proteins out of the cell. As an active transport mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, endocytosis, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive means. Exocytosis is the process by which a large amount of molecules are released thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structure at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

In exocytosis, membrane-bound secretory vesicles are carried to the cell membrane, where they dock and fuse at porosomes and their contents (i.e., water-soluble molecules) are secreted into the extracellular environment. This secretion is possible because the vesicle transiently fuses with the plasma membrane. In the context of neurotransmission, neurotransmitters are typically released from synaptic vesicles into the synaptic cleft via exocytosis however, neurotransmitters can also be released via reverse transport through membrane transport proteins.

Forms Edit

Autocrine Edit

Autocrine signaling involves a cell secreting a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell itself. [17] This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

Paracrine Edit

In paracrine signaling, a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action), as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system juxtacrine interactions and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. [18] Neurotransmitters represent another example of a paracrine signal.

Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. [19] Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling. [20]

Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set of receptors and pathways. In fact, different organs in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development. [21] The highly conserved receptors and pathways can be organized into four major families based on similar structures: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.

Endocrine Edit

Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Endocrine signaling involves the release of hormones by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland and the adrenal glands. The study of the endocrine system and its disorders is known as endocrinology.

Juxtacrine Edit

Juxtacrine signaling is a type of cell–cell or cell–extracellular matrix signaling in multicellular organisms that requires close contact. There are three types:

  1. A membrane ligand (protein, oligosaccharide, lipid) and a membrane protein of two adjacent cells interact.
  2. A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
  3. An extracellular matrixglycoprotein and a membrane protein interact.

Additionally, in unicellular organisms such as bacteria, juxtacrine signaling means interactions by membrane contact. Juxtacrine signaling has been observed for some growth factors, cytokine and chemokine cellular signals, playing an important role in the immune response.

Cells receive information from their neighbors through a class of proteins known as receptors. Receptors may bind with some molecules (ligands) or may interact with physical agents like light, mechanical temperature, pressure, etc. Reception occurs when the target cell (any cell with a receptor protein specific to the signal molecule) detects a signal, usually in the form of a small, water-soluble molecule, via binding to a receptor protein on the cell surface, or once inside the cell, the signaling molecule can bind to intracellular receptors, other elements, or stimulate enzyme activity (e.g. gasses), as in intracrine signaling.

Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects. In many mammals, early embryo cells exchange signals with cells of the uterus. [22] In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. [23] For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) into their environment. The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating. [24]

Cell surface receptors Edit

Cell surface receptors play an essential role in the biological systems of single- and multi-cellular organisms and malfunction or damage to these proteins is associated with cancer, heart disease, and asthma. [25] These trans-membrane receptors are able to transmit information from outside the cell to the inside because they change conformation when a specific ligand binds to it. By looking at three major types of receptors: Ion channel linked receptors, G protein–coupled receptors, and enzyme-linked receptors).

Ion channel linked receptors Edit

Ion channel linked receptors are a group of transmembrane ion-channel proteins which open to allow ions such as Na + , K + , Ca 2+ , and/or Cl − to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter. [26] [27] [28]

When a presynaptic neuron is excited, it releases a neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these receptors are ligand-gated ion channels, a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response.

These receptor proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.

G protein–coupled receptors Edit

G protein-coupled receptors are a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. [29] Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed. [29]

G protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates, [30] and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases.

There are two principal signal transduction pathways involving the G protein-coupled receptors: cAMP signal pathway and phosphatidylinositol signal pathway. [31] When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13). [32] : 1160

G protein-coupled receptors are an important drug target and approximately 34% [33] of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018 [update] . [33] It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of the pharmaceutical research. [29]

Enzyme-linked receptors Edit

Enzyme-linked receptors (or catalytic receptors) are transmembrane receptor that, upon activation by an extracellular ligand, causes enzymatic activity on the intracellular side. [34] Hence a catalytic receptor is an integral membrane protein possessing both enzymatic, catalytic, and receptor functions. [35]

They have two important domains, an extra-cellular ligand binding domain and an intracellular domain, which has a catalytic function and a single transmembrane helix. The signaling molecule binds to the receptor on the outside of the cell and causes a conformational change on the catalytic function located on the receptor inside the cell. Examples of the enzymatic activity include:

Intracellular receptors Edit

Steroid hormone receptor Edit

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) [37] and 3-ketosteroids (group NR3C). [38] In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

When binding to the signaling molecule, the receptor protein changes in some way and starts the process of transduction, which can occur in a single step or as a series of changes in a sequence of different molecules (called a signal transduction pathway). The molecules that compose these pathways are known as relay molecules. The multistep process of the transduction stage is often composed of the activation of proteins by addition or removal of phosphate groups or even the release of other small molecules or ions that can act as messengers. The amplifying of a signal is one of the benefits to this multiple step sequence. Other benefits include more opportunities for regulation than simpler systems do and the fine- tuning of the response, in both unicellular and multicellular organism. [15]

In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For example, the neurotransmitter GABA can activate a cell surface receptor that is part of an ion channel. GABA binding to a GABAA receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABAA receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate physiological effect of the ligand on the cell's behavior is produced. Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway. [39]

A more complex signal transduction pathway is shown in Figure 3. This pathway involves changes of protein–protein interactions inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. Several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. This phosphorylation can generate a binding site for a different protein and thus induce protein–protein interaction. In Figure 3, the ligand (called epidermal growth factor, or EGF) binds to the receptor (called EGFR). This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an adaptor protein (GRB2), which couples the signal to further downstream signaling processes. For example, one of the signal transduction pathways that are activated is called the mitogen-activated protein kinase (MAPK) pathway. The signal transduction component labeled as "MAPK" in the pathway was originally called "ERK," so the pathway is called the MAPK/ERK pathway. The MAPK protein is an enzyme, a protein kinase that can attach phosphate to target proteins such as the transcription factor MYC and, thus, alter gene transcription and, ultimately, cell cycle progression. Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal transduction pathway. [ citation needed ]

Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance, the hedgehog protein activates different genes, depending on the amount of hedgehog protein present. [ citation needed ]

Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways. [ citation needed ]

A specific cellular response is the result of the transduced signal in the final stage of cell signaling. This response can essentially be any cellular activity that is present in a body. It can spur the rearrangement of the cytoskeleton, or even as catalysis by an enzyme. These three steps of cell signaling all ensure that the right cells are behaving as told, at the right time, and in synchronization with other cells and their own functions within the organism. At the end, the end of a signal pathway leads to the regulation of a cellular activity. This response can take place in the nucleus or in the cytoplasm of the cell. A majority of signaling pathways control protein synthesis by turning certain genes on and off in the nucleus. [40]

In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc. [41] In quorum sensing, which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response. In this context, the signaling molecules are called autoinducers. [42] [43] [44] This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. [42] [45] Bacteria also use contact-dependent signaling, notably to limit their growth. [46]

Signaling molecules used by multicellular organisms are often called pheromones. They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction. [47]

Short-term cellular responses Edit

Brief overview of some signaling pathways (based on receptor families) that result in short-acting cellular responses
Receptor Family Example of Ligands/ activators (Bracket: receptor for it) Example of effectors Further downstream effects
Ligand Gated Ion Channels Acetylcholine
(Such as Nicotinic acetylcholine receptor),
Changes in membrane permeability Change in membrane potential
Seven Helix Receptor Light(Rhodopsin),
Dopamine (Dopamine receptor),
GABA (GABA receptor),
Prostaglandin (prostaglandin receptor) etc.
Trimeric G protein Adenylate Cyclase,
cGMP phosphodiesterase,
G-protein gated ion channel, etc.
Two Component Diverse activators Histidine Kinase Response Regulator - flagellar movement, Gene expression
Membrane Guanylyl Cyclase Atrial natriuretic peptide,
Sea urching egg peptide etc.
cGMP Regulation of Kinases and channels- Diverse actions
Cytoplasmic Guanylyl cyclase Nitric Oxide(Nitric oxide receptor) cGMP Regulation of cGMP Gated channels, Kinases
Integrins Fibronectins, other extracellular matrix proteins Nonreceptor tyrosine kinase Diverse response

Regulating gene activity Edit

Brief overview of some signaling pathways (based on receptor families) that control gene activity
Frizzled (Special type of 7Helix receptor) Wnt Dishevelled, axin - APC, GSK3-beta - Beta catenin Gene expression
Two Component Diverse activators Histidine Kinase Response Regulator - flagellar movement, Gene expression
Receptor Tyrosine Kinase Insulin (insulin receptor),
EGF (EGF receptor),
FGF-Alpha, FGF-Beta, etc (FGF-receptors)
Ras, MAP-kinases, PLC, PI3-Kinase Gene expression change
Cytokine receptors Erythropoietin,
Growth Hormone (Growth Hormone Receptor),
IFN-Gamma (IFN-Gamma receptor) etc
JAK kinase STAT transcription factor - Gene expression
Tyrosine kinase Linked- receptors MHC-peptide complex - TCR, Antigens - BCR Cytoplasmic Tyrosine Kinase Gene expression
Receptor Serine/Threonine Kinase Activin(activin receptor),
Inhibin,
Bone-morphogenetic protein(BMP Receptor),
TGF-beta
Smad transcription factors Control of gene expression
Sphingomyelinase linked receptors IL-1(IL-1 receptor),
TNF (TNF-receptors)
Ceramide activated kinases Gene expression
Cytoplasmic Steroid receptors Steroid hormones,
Thyroid hormones,
Retinoic acid etc
Work as/ interact with transcription factors Gene expression

Notch signaling pathway Edit

Notch is a cell surface protein that functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. Ligand receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication. [52] notch acts as a receptor for ligands that are expressed on adjacent cells. While some receptors are cell-surface proteins, others are found inside cells. For example, estrogen is a hydrophobic molecule that can pass through the lipid bilayer of the membranes. As part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be activated by estrogen produced in the ovaries.

In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. As shown in Figure 2, the activation of Notch can cause the Notch protein to be altered by a protease. Part of the Notch protein is released from the cell surface membrane and takes part in gene regulation. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types. [53] [54] Emerging methods for single-cell mass-spectrometry analysis promise to enable studying signal transduction with single-cell resolution. [55]

In notch signaling, direct contact between cells allows for precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell. [56]


Coordination of hormonal signaling and nutrient metabolism drives critical life-cycle transition

An adult fruit fly emerging from a pupa. A RIKEN researcher has investigated the role steroid signaling plays in glucose metabolism during the transition to the pupal stage. Credit: Dr Jeremy Burgess/Science Photo Library

A biologist at RIKEN has discovered the way in which steroid signaling regulates the breakdown of sugar molecules in fruit flies so as to provide the energy larvae need to enter the pupal stage. This finding could have much wider implications that may extend to life-stage changes in people.

Steroid hormones regulate many developmental transitions in animals, from metamorphosis in insects to puberty in people. Yet the compounds that determine the energy metabolism in these biological events have long been overlooked.

"Considerable changes in metabolism and body composition also occur in humans, first during embryonic development and then on through adolescence," notes Takashi Nishimura of the RIKEN Center for Biosystems Dynamics Research. "Hence, my work linking steroids and nutrients in flies may contribute to a deeper understanding of metabolic changes specific to life stages in general."

In his present study, Nishimura focused on the 12-hour window after fruit-fly larvae first build a hardened exoskeleton around their maggoty bodies and enter the pupal stage, during which the adult body forms. This process kicks off with a pulse of steroid production. Nishimura showed that the steroid then interacts with a hormone receptor to activate an enzyme involved in converting a sugar found in the blood-like hemolymph of flies into glucose—an essential energy source needed to make the building blocks and cellular materials as larvae transform into adults.

The additional glucose not only fuels these developmental changes it also spurs the synthesis of more steroid hormone, a cue needed to complete the transition to a pupa.

The findings thus reveal the tight connection between metabolism and hormonal signaling in a manner that is highly regulated across temporal scales. They also highlight how nutrient metabolism is mechanistically linked to cellular and developmental programs through both its bioenergetic and messenger functions.

"This developmental transition is elegantly coupled with nutrient metabolism through the action of steroid hormone, a biological system that provides cellular energy and materials when needed," Nishimura explains.

Nishimura's demonstration of the complex and interconnected functions of metabolism and hormones in the developing fruit fly, a laboratory model, could also help to account for diseased states, such as cancer, that occur when the delicate balance of these processes goes awry. "Metamorphosis is specific to insects," Nishimura notes, "But steroid-driven relevant phenomena in mammals are common, both for health and disease." His findings could thus have far-reaching consequences for biology broadly, including our own.


Hormones: Cell Signaling, Definition and Chemical Nature of Hormones

Living organisms control and coordinate their activities through complex chemical signals.

In multicellular organisms adjacent cells communicate through plasmodesmata (in plants) and gap junctions (in animals).

But, a cell can communicate distant cells by releasing variety of signal molecules such as paracrine signals (neurohormones), endocrine signals (hormones), synaptic signals (neurotransmitters) and gaseous signals (e.g. NO, Nitric Oxide).

Many organisms release Pheromones that alter the behaviour of other organisms of the same species. For example, some algae and animals release pheromones to attract opposite sex. Some strains of Streptococcus faecalis, Gram-positive bacteria secrete pheromones that induce conjugation. The signal molecules bind to specific receptor proteins on or within the cell surface which induce or suppress gene expression, differentiation and metabolism.

Hormones are organic compounds, naturally secreted at low concentration by endocrine cells that exert an influence on physiological processes in multi-cellular organisms. Hormones are also called chemical messengers, information molecules or endocrine signals. The hormones, in general, are stimulatory in action. The hormones having inhibitory actions are called chalones. Bayliss and Straling (1904) coined the term ‘Hormone’ to describe the nature of secretion, the first animal hormone discovered. Went (1928) discovered the first plant hormone i.e. auxin.

Chemical Nature of Hormones:

On the basis of chemical composition, hormones are classified into following types:

These are derived from amino acids tyrosine and tryptophan and have amino group (-NH2). E.g. thyroxine, epinephrine, nor-epinephrine, histamine, etc.

(b) Steroid hormones:

These are derived from cholesterol, e.g.. Androgens, estrogens, progesterone etc.

(c) Polypeptide hormones:

They composed of less than 100 amino acids, For example, short peptide hormones are oxytocin, ADH (antidiuretic hormone), MSH (melanocyte stimulating hormone). The long peptide hormones are insulin, glucagons, ACTH, parthormone etc.

(d) Proteinous hormones:

Generally composed of more than 100 amino acids, e.g., LH, FSH, STH, The LH and FSH are glycoproteins hormones.

(e) Ecosanoids (Gr. ecosn = 20):

These are derived from arachidonic acid, a C-20 fatty acid with 4 double bonds, e.g., prostaglandins, thrombaxanes and leukotriene’s. These are called local hormones because they are short lived and have autocrine and paracrine effect.

On the basis of solubility, hormones may be either lipophilic or Hpophobic. The lipophilic hormones are fat soluble, e.g., steroid hormones, thyroxin and renenoids. All other hormones are hydrophilic that are water-soluble and bind to cell surface receptor for action.

On the basis of distance over which they act, hormones are of following types:

They act on same cells from which they release, e.g., Interleukins (1L- 1,2) which stimulate T-cell proliferation.

(ii) Paracrine hormones:

They act on adjacent cells of their secretion, e.g., prostaglandins.

(iii) Endocrine hormones:

They act on distant cells from the side of their release, e.g., insulin.

(f) Brassinosteroide (= Brassins, BRs):

They are natural growth promoters synthesized from campesterol. They are structurally similar to animal steroid hormones. They were first isolated by Grove et al (1979) in pollens of Brassica napus (rape seed). To date 40 free BRs and 4 BR-conjugates have been discovered. They found in wide range of plant species, in algae, pteridophytes, gymnosperms, and angiosperms. They are synthesized in all parts of plants and mostly in immature seeds, roots and leaves. Brassinosteroides promote cell division, cell elongation, bending of stem, development of vascular tissues and reproductive organs.

They are oligosaccharides of hormonal properties released from plant cell walls. They elicit defense responses against fungal attack. They are known to inhibit the auxin stimulated apical dominance of pea stems, root formation in tobacco etc.

They are the compounds having more than one amine groups, synthesized from amino acids lysine, arginine, e.g. putrescine and spermidine etc. They have some effect in cell division growth and development. Putrescine H2N-(CH2) NH2 level increase in stress response.

Organic compounds or bio-molecules are the universal occurrence of all living organisms. For analysis of the types of organic compounds found in living organisms, take any living tissue (a piece of vegetable or liver etc.) and grind with trichloroacetic acid to get thick slurry or homogenate. The process of grinding to disrupt the cells is called homogenization, which is usually done in a high speed blender or using mortar and pestle.

When the homogenate is filtered we would get 2 fractions i.e. a filtrate called acid-soluble pool, and the retentate called acid-insoluble pool. The biomolecules found in both the pools (fractions). The acid soluble pool usually contains the cytoplasmic composition, while the acid insoluble fraction contains macromolecules from cytosol and organelles.

On the basis of molecular weight (MW) and solubility, biomolecules are of 2 types, micro-molecules and macromolecules. Micro-molecules are low MW organic compounds (less than 100 Dalton) usually found in acid soluble pool. For example, sugars, amino acids, nucleotides vitamins etc.

Micro-molecules are often called building block molecules or monomers which covalently linked to each other to form macromolecules or polymers. Macromolecules are high MW (about 1000 Dalton or above) organic compounds usually found in acid -insoluble fraction or macromolecular fraction e.g., proteins, nucleic acids, polysaccharides and lipids.

Though lipids found in macromolecular fraction, they are actually micro-molecules, whose molecular weights d or A exceeds 800 Da. The nucleic acids and proteins are called informational molecules. The large size and 3D-shape of macromolecules enables them to function as structural components, enzymes, nutrient .stores, molecular messenger and sources of genetic information.


28.1 Types of Hormones

In this section, you will explore the following questions:

  • What are the different types of hormones?
  • What is the role of hormones in maintaining homeostasis?

Connection for AP ® Courses

Much information about the various organ systems of animals is not within the scope for AP ® . The endocrine system, however, was selected for in-depth study because an animal’s ability to detect, transmit and respond to information is critical to survival. The endocrine and nervous systems work together to maintain homeostasis and adjust physiological activity when external or internal environmental conditions change. The nervous system works by generating action potentials along neurons the endocrine system uses chemical messengers called hormones that are released from glands, travel to target cells, and elicit a response by the target cell. For AP ® you are not expected to memorize a laundry list of the various endocrine glands, their hormones, and the effects of each hormone. You should be able to interpret, however, a diagram that shows the activity of a hormonal signal. We will briefly describe a few of these examples in How Hormones Work.

There are three types of hormones classified based on molecular structure and properties. (We explored structure/function relationships at the molecular level in the chapter on Biological Macromolecules.) Lipid-derived hormones are lipid-soluble and can diffuse across cell membranes because they are non-polar. Most lipid hormones are derived from cholesterol examples include steroids such as estrogen and testosterone. Because lipid hormones can diffuse across cell membranes, their receptors are located in the cytoplasm of target cells. The amino acid-derived hormones are relatively small molecules derived from the amino acids tyrosine and tryptophan examples include epinephrine, norepinephrine, thyroxin, and melatonin. Peptide hormones such as oxytocin and growth hormone consist of polypeptide chains of amino acids. Because these hormones are water-soluble and insoluble in lipids, they cannot pass through the plasma membrane of cells their receptors are found on the surface of the target cells.

Information presented and the examples highlighted in the section support concepts outlined in Big Idea 3 and Big Idea 4 of the AP ® Biology Curriculum Framework. The AP ® Learning Objectives listed in the Curriculum Framework provide a transparent foundation for the AP ® Biology course, an inquiry-based laboratory experience, instructional activities, and AP ® exam questions. A learning objective merges required content with one or more of the seven science practices.

Big Idea 3 Living systems store, retrieve, transmit and respond to information essential to life processes.
Enduring Understanding 3.D Cells communicate by generating, transmitting and receiving chemical signals.
Essential Knowledge 3.D.1 Cell communication processes share common features that reflect a shared evolutionary history.
Science Practice 6.2 The student can construct explanations of phenomena based on evidence produced through scientific practices.
Learning Objective 3.33 The student is able to use representations and models to describe features of a cell signaling pathway.
Big Idea 4 Biological systems interact, and these systems and their interactions possess complex properties.
Enduring Understanding 4.A Interactions within biological systems lead to complex properties.
Essential Knowledge 4.A.1 The subcomponents of biological molecules and their sequence determine the properties of that molecule.
Science Practice 7.1 The student can connect phenomena and models across spatial and temporal scales.
Learning Objective 4.1 The student is able to explain the connection between the sequence and subcomponents of a biological polymer and its properties.

Maintaining homeostasis within the body requires the coordination of many different systems and organs. Communication between neighboring cells, and between cells and tissues in distant parts of the body, occurs through the release of chemicals called hormones. Hormones are released into body fluids (usually blood) that carry these chemicals to their target cells. At the target cells, which are cells that have a receptor for a signal or ligand from a signal cell, the hormones elicit a response. The cells, tissues, and organs that secrete hormones make up the endocrine system. Examples of glands of the endocrine system include the adrenal glands, which produce hormones such as epinephrine and norepinephrine that regulate responses to stress, and the thyroid gland, which produces thyroid hormones that regulate metabolic rates.

Although there are many different hormones in the human body, they can be divided into three classes based on their chemical structure: lipid-derived, amino acid-derived, and peptide (peptide and proteins) hormones. One of the key distinguishing features of lipid-derived hormones is that they can diffuse across plasma membranes whereas the amino acid-derived and peptide hormones cannot.

Lipid-Derived Hormones (or Lipid-soluble Hormones)

Most lipid hormones are derived from cholesterol and thus are structurally similar to it, as illustrated in Figure 28.2. The primary class of lipid hormones in humans is the steroid hormones. Chemically, these hormones are usually ketones or alcohols their chemical names will end in “-ol” for alcohols or “-one” for ketones. Examples of steroid hormones include estradiol, which is an estrogen, or female sex hormone, and testosterone, which is an androgen, or male sex hormone. These two hormones are released by the female and male reproductive organs, respectively. Other steroid hormones include aldosterone and cortisol, which are released by the adrenal glands along with some other types of androgens. Steroid hormones are insoluble in water, and they are transported by transport proteins in blood. As a result, they remain in circulation longer than peptide hormones. For example, cortisol has a half-life of 60 to 90 minutes, while epinephrine, an amino acid derived-hormone, has a half-life of approximately one minute.

Amino Acid-Derived Hormones

The amino acid-derived hormones are relatively small molecules that are derived from the amino acids tyrosine and tryptophan, shown in Figure 28.3. If a hormone is amino acid-derived, its chemical name will end in “-ine”. Examples of amino acid-derived hormones include epinephrine and norepinephrine, which are synthesized in the medulla of the adrenal glands, and thyroxine, which is produced by the thyroid gland. The pineal gland in the brain makes and secretes melatonin which regulates sleep cycles.

Peptide Hormones

The structure of peptide hormones is that of a polypeptide chain (chain of amino acids). The peptide hormones include molecules that are short polypeptide chains, such as antidiuretic hormone and oxytocin produced in the brain and released into the blood in the posterior pituitary gland. This class also includes small proteins, like growth hormones produced by the pituitary, and large glycoproteins such as follicle-stimulating hormone produced by the pituitary. Figure 28.4 illustrates these peptide hormones.

Secreted peptides like insulin are stored within vesicles in the cells that synthesize them. They are then released in response to stimuli such as high blood glucose levels in the case of insulin. Amino acid-derived and polypeptide hormones are water-soluble and insoluble in lipids. These hormones cannot pass through plasma membranes of cells therefore, their receptors are found on the surface of the target cells.


BIO 140 - Human Biology I - Textbook

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Chapter 36

Hormones

  • Identify the three major classes of hormones on the basis of chemical structure
  • Compare and contrast intracellular and cell membrane hormone receptors
  • Describe signaling pathways that involve cAMP and IP3
  • Identify several factors that influence a target cell&rsquos response
  • Discuss the role of feedback loops and humoral, hormonal, and neural stimuli in hormone control

Although a given hormone may travel throughout the body in the bloodstream, it will affect the activity only of its target cells that is, cells with receptors for that particular hormone. Once the hormone binds to the receptor, a chain of events is initiated that leads to the target cell&rsquos response. Hormones play a critical role in the regulation of physiological processes because of the target cell responses they regulate. These responses contribute to human reproduction, growth and development of body tissues, metabolism, fluid, and electrolyte balance, sleep, and many other body functions. The major hormones of the human body and their effects are identified in Table 1.

Table 1: Endocrine Glands and Their Major Hormones

Endocrine gland Associated hormones Chemical class Effect
Pituitary (anterior) Growth hormone (GH) Protein Promotes growth of body tissues
Pituitary (anterior) Prolactin (PRL) Peptide Promotes milk production
Pituitary (anterior) Thyroid-stimulating hormone (TSH) Glycoprotein Stimulates thyroid hormone release
Pituitary (anterior) Adrenocorticotropic hormone (ACTH) Peptide Stimulates hormone release by adrenal cortex
Pituitary (anterior) Follicle-stimulating hormone (FSH) Glycoprotein Stimulates gamete production
Pituitary (anterior) Luteinizing hormone (LH) Glycoprotein Stimulates androgen production by gonads
Pituitary (posterior) Antidiuretic hormone (ADH) Peptide Stimulates water reabsorption by kidneys
Pituitary (posterior) Oxytocin Peptide Stimulates uterine contractions during childbirth
Thyroid Thyroxine (T4), triiodothyronine (T3) Amine Stimulate basal metabolic rate
Thyroid Calcitonin Peptide Reduces blood Ca 2+ levels
Parathyroid Parathyroid hormone (PTH) Peptide Increases blood Ca 2+ levels
Adrenal (cortex) Aldosterone Steroid Increases blood Na + levels
Adrenal (cortex) Cortisol, corticosterone, cortisone Steroid Increase blood glucose levels
Adrenal (medulla) Epinephrine, norepinephrine Amine Stimulate fight-or-flight response
Pineal Melatonin Amine Regulates sleep cycles
Pancreas Insulin Protein Reduces blood glucose levels
Pancreas Glucagon Protein Increases blood glucose levels
Testes Testosterone Steroid Stimulates development of male secondary sex characteristics and sperm production
Ovaries Estrogens and progesterone Steroid Stimulate development of female secondary sex characteristics and prepare the body for childbirth

Types of Hormones

The hormones of the human body can be divided into two major groups on the basis of their chemical structure. Hormones derived from amino acids include amines, peptides, and proteins. Those derived from lipids include steroids (Figure 1). These chemical groups affect a hormone&rsquos distribution, the type of receptors it binds to, and other aspects of its function.

Amine Hormones

Hormones derived from the modification of amino acids are referred to as amine hormones. Typically, the original structure of the amino acid is modified such that a &ndashCOOH, or carboxyl, group is removed, whereas the , or amine, group remains.

Amine hormones are synthesized from the amino acids tryptophan or tyrosine. An example of a hormone derived from tryptophan is melatonin, which is secreted by the pineal gland and helps regulate circadian rhythm. Tyrosine derivatives include the metabolism-regulating thyroid hormones, as well as the catecholamines, such as epinephrine, norepinephrine, and dopamine. Epinephrine and norepinephrine are secreted by the adrenal medulla and play a role in the fight-or-flight response, whereas dopamine is secreted by the hypothalamus and inhibits the release of certain anterior pituitary hormones.

Peptide and Protein Hormones

Whereas the amine hormones are derived from a single amino acid, peptide and protein hormones consist of multiple amino acids that link to form an amino acid chain. Peptide hormones consist of short chains of amino acids, whereas protein hormones are longer polypeptides. Both types are synthesized like other body proteins: DNA is transcribed into mRNA, which is translated into an amino acid chain.

Examples of peptide hormones include antidiuretic hormone (ADH), a pituitary hormone important in fluid balance, and atrial-natriuretic peptide, which is produced by the heart and helps to decrease blood pressure. Some examples of protein hormones include growth hormone, which is produced by the pituitary gland, and follicle-stimulating hormone (FSH), which has an attached carbohydrate group and is thus classified as a glycoprotein. FSH helps stimulate the maturation of eggs in the ovaries and sperm in the testes.

Steroid Hormones

The primary hormones derived from lipids are steroids. Steroid hormones are derived from the lipid cholesterol. For example, the reproductive hormones testosterone and the estrogens&mdashwhich are produced by the gonads (testes and ovaries)&mdashare steroid hormones. The adrenal glands produce the steroid hormone aldosterone, which is involved in osmoregulation, and cortisol, which plays a role in metabolism.

Like cholesterol, steroid hormones are not soluble in water (they are hydrophobic). Because blood is water-based, lipid-derived hormones must travel to their target cell bound to a transport protein. This more complex structure extends the half-life of steroid hormones much longer than that of hormones derived from amino acids. A hormone&rsquos half-life is the time required for half the concentration of the hormone to be degraded. For example, the lipid-derived hormone cortisol has a half-life of approximately 60 to 90 minutes. In contrast, the amino acid&ndashderived hormone epinephrine has a half-life of approximately one minute.

Pathways of Hormone Action

The message a hormone sends is received by a hormone receptor , a protein located either inside the cell or within the cell membrane. The receptor will process the message by initiating other signaling events or cellular mechanisms that result in the target cell&rsquos response. Hormone receptors recognize molecules with specific shapes and side groups, and respond only to those hormones that are recognized. The same type of receptor may be located on cells in different body tissues, and trigger somewhat different responses. Thus, the response triggered by a hormone depends not only on the hormone, but also on the target cell.

Once the target cell receives the hormone signal, it can respond in a variety of ways. The response may include the stimulation of protein synthesis, activation or deactivation of enzymes, alteration in the permeability of the cell membrane, altered rates of mitosis and cell growth, and stimulation of the secretion of products. Moreover, a single hormone may be capable of inducing different responses in a given cell.

Pathways Involving Intracellular Hormone Receptors

Intracellular hormone receptors are located inside the cell. Hormones that bind to this type of receptor must be able to cross the cell membrane. Steroid hormones are derived from cholesterol and therefore can readily diffuse through the lipid bilayer of the cell membrane to reach the intracellular receptor (Figure 2). Thyroid hormones, which contain benzene rings studded with iodine, are also lipid-soluble and can enter the cell.

The location of steroid and thyroid hormone binding differs slightly: a steroid hormone may bind to its receptor within the cytosol or within the nucleus. In either case, this binding generates a hormone-receptor complex that moves toward the chromatin in the cell nucleus and binds to a particular segment of the cell&rsquos DNA. In contrast, thyroid hormones bind to receptors already bound to DNA. For both steroid and thyroid hormones, binding of the hormone-receptor complex with DNA triggers transcription of a target gene to mRNA, which moves to the cytosol and directs protein synthesis by ribosomes.

Figure 2: A steroid hormone directly initiates the production of proteins within a target cell. Steroid hormones easily diffuse through the cell membrane. The hormone binds to its receptor in the cytosol, forming a receptor&ndashhormone complex. The receptor&ndashhormone complex then enters the nucleus and binds to the target gene on the DNA. Transcription of the gene creates a messenger RNA that is translated into the desired protein within the cytoplasm.

Pathways Involving Cell Membrane Hormone Receptors

Hydrophilic, or water-soluble, hormones are unable to diffuse through the lipid bilayer of the cell membrane and must therefore pass on their message to a receptor located at the surface of the cell. Except for thyroid hormones, which are lipid-soluble, all amino acid&ndashderived hormones bind to cell membrane receptors that are located, at least in part, on the extracellular surface of the cell membrane. Therefore, they do not directly affect the transcription of target genes, but instead initiate a signaling cascade that is carried out by a molecule called a second messenger . In this case, the hormone is called a first messenger .

The second messenger used by most hormones is cyclic adenosine monophosphate (cAMP) . In the cAMP second messenger system, a water-soluble hormone binds to its receptor in the cell membrane (Step 1 in Figure 3). This receptor is associated with an intracellular component called a G protein , and binding of the hormone activates the G-protein component (Step 2). The activated G protein in turn activates an enzyme called adenylyl cyclase , also known as adenylate cyclase (Step 3), which converts adenosine triphosphate (ATP) to cAMP (Step 4). As the second messenger, cAMP activates a type of enzyme called a protein kinase that is present in the cytosol (Step 5). Activated protein kinases initiate a phosphorylation cascade , in which multiple protein kinases phosphorylate (add a phosphate group to) numerous and various cellular proteins, including other enzymes (Step 6).

Figure 3: Water-soluble hormones cannot diffuse through the cell membrane. These hormones must bind to a surface cell-membrane receptor. The receptor then initiates a cell-signaling pathway within the cell involving G proteins, adenylyl cyclase, the secondary messenger cyclic AMP (cAMP), and protein kinases. In the final step, these protein kinases phosphorylate proteins in the cytoplasm. This activates proteins in the cell that carry out the changes specified by the hormone.

The phosphorylation of cellular proteins can trigger a wide variety of effects, from nutrient metabolism to the synthesis of different hormones and other products. The effects vary according to the type of target cell, the G proteins and kinases involved, and the phosphorylation of proteins. Examples of hormones that use cAMP as a second messenger include calcitonin, which is important for bone construction and regulating blood calcium levels glucagon, which plays a role in blood glucose levels and thyroid-stimulating hormone, which causes the release of T3 and T4 from the thyroid gland.

Overall, the phosphorylation cascade significantly increases the efficiency, speed, and specificity of the hormonal response, as thousands of signaling events can be initiated simultaneously in response to a very low concentration of hormone in the bloodstream. However, the duration of the hormone signal is short, as cAMP is quickly deactivated by the enzyme phosphodiesterase (PDE) , which is located in the cytosol. The action of PDE helps to ensure that a target cell&rsquos response ceases quickly unless new hormones arrive at the cell membrane.

Importantly, there are also G proteins that decrease the levels of cAMP in the cell in response to hormone binding. For example, when growth hormone&ndashinhibiting hormone (GHIH), also known as somatostatin, binds to its receptors in the pituitary gland, the level of cAMP decreases, thereby inhibiting the secretion of human growth hormone.

Not all water-soluble hormones initiate the cAMP second messenger system. One common alternative system uses calcium ions as a second messenger. In this system, G proteins activate the enzyme phospholipase C (PLC), which functions similarly to adenylyl cyclase. Once activated, PLC cleaves a membrane-bound phospholipid into two molecules: diacylglycerol (DAG) and inositol triphosphate (IP3) . Like cAMP, DAG activates protein kinases that initiate a phosphorylation cascade. At the same time, IP3 causes calcium ions to be released from storage sites within the cytosol, such as from within the smooth endoplasmic reticulum. The calcium ions then act as second messengers in two ways: they can influence enzymatic and other cellular activities directly, or they can bind to calcium-binding proteins, the most common of which is calmodulin. Upon binding calcium, calmodulin is able to modulate protein kinase within the cell. Examples of hormones that use calcium ions as a second messenger system include angiotensin II, which helps regulate blood pressure through vasoconstriction, and growth hormone&ndashreleasing hormone (GHRH), which causes the pituitary gland to release growth hormones.

Factors Affecting Target Cell Response

You will recall that target cells must have receptors specific to a given hormone if that hormone is to trigger a response. But several other factors influence the target cell response. For example, the presence of a significant level of a hormone circulating in the bloodstream can cause its target cells to decrease their number of receptors for that hormone. This process is called downregulation , and it allows cells to become less reactive to the excessive hormone levels. When the level of a hormone is chronically reduced, target cells engage in upregulation to increase their number of receptors. This process allows cells to be more sensitive to the hormone that is present. Cells can also alter the sensitivity of the receptors themselves to various hormones.

Two or more hormones can interact to affect the response of cells in a variety of ways. The three most common types of interaction are as follows:

  • The permissive effect, in which the presence of one hormone enables another hormone to act. For example, thyroid hormones have complex permissive relationships with certain reproductive hormones. A dietary deficiency of iodine, a component of thyroid hormones, can therefore affect reproductive system development and functioning.
  • The synergistic effect, in which two hormones with similar effects produce an amplified response. In some cases, two hormones are required for an adequate response. For example, two different reproductive hormones&mdashFSH from the pituitary gland and estrogens from the ovaries&mdashare required for the maturation of female ova (egg cells).
  • The antagonistic effect, in which two hormones have opposing effects. A familiar example is the effect of two pancreatic hormones, insulin and glucagon. Insulin increases the liver&rsquos storage of glucose as glycogen, decreasing blood glucose, whereas glucagon stimulates the breakdown of glycogen stores, increasing blood glucose.

Regulation of Hormone Secretion

To prevent abnormal hormone levels and a potential disease state, hormone levels must be tightly controlled. The body maintains this control by balancing hormone production and degradation. Feedback loops govern the initiation and maintenance of most hormone secretion in response to various stimuli.

Role of Feedback Loops

The contribution of feedback loops to homeostasis will only be briefly reviewed here. Positive feedback loops are characterized by the release of additional hormone in response to an original hormone release. The release of oxytocin during childbirth is a positive feedback loop. The initial release of oxytocin begins to signal the uterine muscles to contract, which pushes the fetus toward the cervix, causing it to stretch. This, in turn, signals the pituitary gland to release more oxytocin, causing labor contractions to intensify. The release of oxytocin decreases after the birth of the child.

The more common method of hormone regulation is the negative feedback loop. Negative feedback is characterized by the inhibition of further secretion of a hormone in response to adequate levels of that hormone. This allows blood levels of the hormone to be regulated within a narrow range. An example of a negative feedback loop is the release of glucocorticoid hormones from the adrenal glands, as directed by the hypothalamus and pituitary gland. As glucocorticoid concentrations in the blood rise, the hypothalamus and pituitary gland reduce their signaling to the adrenal glands to prevent additional glucocorticoid secretion (Figure 4).

Figure 4: The release of adrenal glucocorticoids is stimulated by the release of hormones from the hypothalamus and pituitary gland. This signaling is inhibited when glucocorticoid levels become elevated by causing negative signals to the pituitary gland and hypothalamus.

Role of Endocrine Gland Stimuli

Reflexes triggered by both chemical and neural stimuli control endocrine activity. These reflexes may be simple, involving only one hormone response, or they may be more complex and involve many hormones, as is the case with the hypothalamic control of various anterior pituitary&ndashcontrolled hormones.

Humoral stimuli are changes in blood levels of non-hormone chemicals, such as nutrients or ions, which cause the release or inhibition of a hormone to, in turn, maintain homeostasis. For example, osmoreceptors in the hypothalamus detect changes in blood osmolarity (the concentration of solutes in the blood plasma). If blood osmolarity is too high, meaning that the blood is not dilute enough, osmoreceptors signal the hypothalamus to release ADH. The hormone causes the kidneys to reabsorb more water and reduce the volume of urine produced. This reabsorption causes a reduction of the osmolarity of the blood, diluting the blood to the appropriate level. The regulation of blood glucose is another example. High blood glucose levels cause the release of insulin from the pancreas, which increases glucose uptake by cells and liver storage of glucose as glycogen.

An endocrine gland may also secrete a hormone in response to the presence of another hormone produced by a different endocrine gland. Such hormonal stimuli often involve the hypothalamus, which produces releasing and inhibiting hormones that control the secretion of a variety of pituitary hormones.

In addition to these chemical signals, hormones can also be released in response to neural stimuli. A common example of neural stimuli is the activation of the fight-or-flight response by the sympathetic nervous system. When an individual perceives danger, sympathetic neurons signal the adrenal glands to secrete norepinephrine and epinephrine. The two hormones dilate blood vessels, increase the heart and respiratory rate, and suppress the digestive and immune systems. These responses boost the body&rsquos transport of oxygen to the brain and muscles, thereby improving the body&rsquos ability to fight or flee.

Everyday Connection

Bisphenol A and Endocrine Disruption

You may have heard news reports about the effects of a chemical called bisphenol A (BPA) in various types of food packaging. BPA is used in the manufacturing of hard plastics and epoxy resins. Common food-related items that may contain BPA include the lining of aluminum cans, plastic food-storage containers, drinking cups, as well as baby bottles and &ldquosippy&rdquo cups. Other uses of BPA include medical equipment, dental fillings, and the lining of water pipes.

Research suggests that BPA is an endocrine disruptor, meaning that it negatively interferes with the endocrine system, particularly during the prenatal and postnatal development period. In particular, BPA mimics the hormonal effects of estrogens and has the opposite effect&mdashthat of androgens. The U.S. Food and Drug Administration (FDA) notes in their statement about BPA safety that although traditional toxicology studies have supported the safety of low levels of exposure to BPA, recent studies using novel approaches to test for subtle effects have led to some concern about the potential effects of BPA on the brain, behavior, and prostate gland in fetuses, infants, and young children. The FDA is currently facilitating decreased use of BPA in food-related materials. Many US companies have voluntarily removed BPA from baby bottles, &ldquosippy&rdquo cups, and the linings of infant formula cans, and most plastic reusable water bottles sold today boast that they are &ldquoBPA free.&rdquo In contrast, both Canada and the European Union have completely banned the use of BPA in baby products.

The potential harmful effects of BPA have been studied in both animal models and humans and include a large variety of health effects, such as developmental delay and disease. For example, prenatal exposure to BPA during the first trimester of human pregnancy may be associated with wheezing and aggressive behavior during childhood. Adults exposed to high levels of BPA may experience altered thyroid signaling and male sexual dysfunction. BPA exposure during the prenatal or postnatal period of development in animal models has been observed to cause neurological delays, changes in brain structure and function, sexual dysfunction, asthma, and increased risk for multiple cancers. In vitro studies have also shown that BPA exposure causes molecular changes that initiate the development of cancers of the breast, prostate, and brain. Although these studies have implicated BPA in numerous ill health effects, some experts caution that some of these studies may be flawed and that more research needs to be done. In the meantime, the FDA recommends that consumers take precautions to limit their exposure to BPA. In addition to purchasing foods in packaging free of BPA, consumers should avoid carrying or storing foods or liquids in bottles with the recycling code 3 or 7. Foods and liquids should not be microwave-heated in any form of plastic: use paper, glass, or ceramics instead.

Chapter Review

Hormones are derived from amino acids or lipids. Amine hormones originate from the amino acids tryptophan or tyrosine. Larger amino acid hormones include peptides and protein hormones. Steroid hormones are derived from cholesterol.

Steroid hormones and thyroid hormone are lipid soluble. All other amino acid&ndashderived hormones are water soluble. Hydrophobic hormones are able to diffuse through the membrane and interact with an intracellular receptor. In contrast, hydrophilic hormones must interact with cell membrane receptors. These are typically associated with a G protein, which becomes activated when the hormone binds the receptor. This initiates a signaling cascade that involves a second messenger, such as cyclic adenosine monophosphate (cAMP). Second messenger systems greatly amplify the hormone signal, creating a broader, more efficient, and faster response.

Hormones are released upon stimulation that is of either chemical or neural origin. Regulation of hormone release is primarily achieved through negative feedback. Various stimuli may cause the release of hormones, but there are three major types. Humoral stimuli are changes in ion or nutrient levels in the blood. Hormonal stimuli are changes in hormone levels that initiate or inhibit the secretion of another hormone. Finally, a neural stimulus occurs when a nerve impulse prompts the secretion or inhibition of a hormone.


Steroid Hormone Receptors and Regulators

Steroid hormone is a steroid that serves as a hormone. It can be divided into two groups: corticosteroids and sex steroids. Within these two classes, they are five types according to their receptors: glucocorticoids, mineralocorticoids, androgens, estrogen and progestogens. In human body, steroid hormones play an important part in metabolism, inflammation, immune functions, salt and water balance, development of sexual characteristics and the ability of withstanding illness and injury. The natural steroid hormones are generally synthesized from cholesterol in the gonads and adrenal glands. These hormones are lipophilic substance. They can pass through the cell membrane as they are fat-soluble, and then bind to steroid hormone receptors (which may be nuclear or cytosolic depending on the steroid hormone) to bring about changes within the cell. Steroid hormones are generally carried in the blood, bound to specific carrier proteins such as sex hormone-binding globulin, corticosteroid-binding globulin and albumin. The binding is beneficial to help improve the hormones’ solubility in water.

Most studies say that hormones can affect cells when they are not bound by serum proteins. In order to be active, steroid hormones must free themselves from their blood-solubilizing proteins and either bind to extracellular receptors, or passively cross the cell membrane and bind to nuclear receptors. This idea is called the free hormone hypothesis. One study has found that these steroid-carrier complexes are bound by Megalin, a membrane receptor, and are then taken into cells via endocytosis. One possible pathway is that once inside the cell these complexes are taken to the lysosome, where the carrier protein is degraded and the steroid hormone is released into the cytoplasm of the target cell.

After the steroid hormones are transported to the target tissues and cells, they bind to the corresponding hormone receptors. Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), and androgen receptor (AR) are classic members of the nuclear receptor superfamily, composing subfamily 3C. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C). In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

Steroid Hormone Receptors and Regulators

Individually and in combination, these four receptors play pivotal roles in some of the most fundamental aspects of physiology such as the stress response, metabolism, immune function, electrolyte homeostasis, growth, development, and reproduction. Multiple signaling pathways have been established for all four receptors, and several common mechanisms have been revealed. One main signaling pathway is achieved by direct DNA binding and transcriptional regulation of responsive genes. Another is achieved through protein-protein interactions, mainly with other transcription factors such as nuclear factor-kB, activator protein-1, or signal transducer and activator of transcriptions, to regulate gene expression patterns. These pathways can be up-regulate or down-regulate gene expression. And they all require ligand activation of the receptor and interplay with multiple protein factors such as chaperone proteins and co-regulator proteins.

The GR, MR, PR, and AR share structural similarities, with all containing three functional domains, i.e., the N-terminal transactivation domain followed by the DNA-binding domain (DBD) and the C-terminal ligand binding domain (LBD). A hinge region links the DBD and the LBD. These four steroid hormone receptors also exemplify the tremendous capacity and precision of endocrine modulatory mechanisms. Patients carrying mutated receptors frequently experience severe complications, and transgenic animals lacking individual receptors frequently cannot reproduce and/or survive. Temporally controlled tissue distribution patterns during developmental stages, reproductive phases, and disease states contribute to the diverse activities of these receptors.GR is expressed in almost all tissues although tissue and cell cycle-specific regulation of GR levels. Glucocorticoids exert a vast of physiological functions via the GR. Glucocorticoids are essential regulators of carbohydrate, protein, and fat metabolism The major glucocorticoid in the human is cortisol, also called hydrocortisone, whereas in rodents the major glucocorticoid is corticosterone. The synthesis and secretion of glucocorticoids by the adrenal cortex are tightly regulated by the hypothalamo-pituitary-adrenal axis, which is susceptible to negative feedback by circulating hormones and exogenous glucocorticoids. MR is expressed in epithelial tissues, such as the distal nephron or colon. Aldosterone can moderate dietary salt intake and the balance of salt ions by regulating the epithelial sodium channel and Na+, K+-ATPase subunit genes. The most physiologically important mineralocorticoid is aldosterone. Aldosterone is synthesized in the adrenal cortex primarily under the regulation of the renin-angiotensin system, potassium status, and ACTH. Progesterone is the most important progestin in humans. It is synthesized in the ovary, testis, and adrenal gland. Substantial amounts are also synthesized and released by the placenta during pregnancy. In addition to having significant hormonal effects, progesterone serves as a precursor in the synthesis of estrogen, androgens, and adrenocortical steroids. PR is expressed in the female generative tract, mammary gland, brain, and pituitary gland. In many cells, estrogen induces expression of PR, and its presence is a common marker for estrogen action in both research and clinical settings. In many biological systems, progestin enhances differentiation and opposes the cell proliferation action of estrogen. In humans, the predominant androgen secreted by the testis or ovary and peripheral conversion of androstenedione produced by the adrenal gland is testosterone. Androgens serve critical functions at different stages of life in the male. During embryonic life, androgens virilize the urogenital tract of the male embryo, and their action is therefore essential for the development of the male phenotype. At puberty, androgens promote the development of secondary sexual characteristics. In addition to stimulating and maintaining sexual function in men, androgens may also be responsible in part for aggressive behaviors. Testosterone and androstenedione are precursors for estrogen biosynthesis. Testosterone and 5-dihydrotesterone also produce androgenic effects via the AR.

Cancer Risk Factors

According to previous studies, researchers find that glucocorticoids are a key to treating certain leukemia and are frequently included in chemotherapy regimens for their antiemetic, antiedema, and palliative properties. The study found that serum cortisol levels in patients with prostate cancer were significantly higher than those in prostate hyperplasia. Preoperative blood cortisol levels in the lung cancer group and the digestive tract cancer group were higher than those in the healthy control group. This may be due to the abnormal metabolism of the cancer itself and the influence of cancer tissue on the body, lead to endocrine or metabolic disorders. In breast cancer and ovarian cancer research, dexamethasone can rapidly inhibit ERK activity in a manner independent of glucocorticoid receptors, and may be involved in the process of inhibiting cell proliferation in human breast cancer cell lines. In the process of inhibition of brain tumors, it is found that the combination of glucocorticoids and various biological effects can inhibit the synthesis and biological effects of vascular endothelial growth factor (VEGF) in tumor cells, inhibit the action of oxygen free radicals, and act on inflammatory mediators and inhibit tumor cell production function. And the presence of the PR acts as a useful prognostic marker in breast cancer irrespective of the patient’s progestational status. Studies suggest that certain progestin plus estrogen replacement regimens in postmenopausal women may increase the incidence of breast cancer. In addition, recurrent prostate cancer seems to result from increased AR signaling caused by increased AR expression in the presence or absence of AR gene amplification. The onset of recurrent prostate cancer seems to involve increasing AR-dependent growth factor signaling that overcomes apoptosis induced by androgen depletion.


Steroid Hormone Action in the Brain: Cross-Talk Between Signalling Pathways

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

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Abstract

Ovarian steroid hormones, oestradiol and progesterone, modulate neuroendocrine functions in the central nervous system, resulting in alterations in physiology and behaviour. The classical model of steroid hormone action assumes that these neural effects are predominantly mediated via their intracellular receptors functioning as ‘ligand-dependent’ transcription factors in the steroid-sensitive neurones regulating genes and genomic networks with profound behavioural consequences. Studies from our laboratory demonstrate that, in addition to their cognate ligands, intracellular steroid receptors can be activated in a ‘ligand-independent’ manner by the neurotransmitter dopamine, which alters the dynamic equilibrium between neuronal phosphatases and kinases. A high degree of cross-talk between membrane-initiated signalling pathways and the classical intracellular signalling pathways mediates hormone-dependent behaviour in mammals. The molecular mechanisms, by which a multitude of signals converge with steroid receptors to delineate a genomic level of cross-talk in brain and behaviour are discussed.


Watch the video: Signaling pathway of steroid hormones (June 2022).


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