We learn in Physiology that during the depolarization phase in the membrane, more sodium channels tend to open as the membrane potential increases i.e., less negative. This is a kind of positive feedback which leads to the action potential and explains the threshold of depolarization that is required for action potential.
So in short, as the membrane potential becomes less negative sodium channels tend to open.
On the other hand there is famous graph from Bertram Katzung, Susan Masters, Anthony Trevor-Basic and Clinical Pharmacology, Edition 12. which shows the dependence of the sodium channel function based on the membrane potential preceding the stimulus.
The fraction of sodium channels available for opening in response to a stimulus is determined by the membrane potential immediately preceding the stimulus. The decrease in the fraction available when the resting potential is depolarized in the absence of a drug (control curve) results from the voltage-dependent closure of h gates in the channels.
Both these cases look pretty contraindicating to me. But I attempted to explain this by the three stages of the Na+ channel.
Case 1 - may be addressing the transition from closed to open channels, i.e., opening of the m gate. (I'm just hypothesizing here so correct me if wrong)
Case 2 - as mentioned in the book, talks of closing of the h gate leading to inactivated gates at higher membrane potentials.
Do case 1 and case 2 happen one after another? Are the voltage ranges for each different? Is my explanation for case 1 correct?
Fenestrations control resting-state block of a voltage-gated sodium channel
Voltage-gated sodium channels initiate electrical signals in nerve and cardiac muscle, where their hyperactivity causes pain and cardiac arrhythmia. Local anesthetics and antiarrhythmic drugs selectively block sodium channels in rapidly firing nerve and muscle cells to relieve these conditions. We studied an ancestral bacterial sodium channel to elucidate the structure of the drug-binding site and the pathway for drug entry to the receptor site. We found that the drug-binding site is located in the center of the transmembrane pore, through which sodium ions move and fenestrations form an access pathway for drug entry directly from the cell membrane. These results show how these widely used drugs block the sodium channel and have important implications for structure-based design of next-generation drugs.
What is a voltage gated sodium ion channel?
A voltage-gated sodium ion channel is a channel that allows only sodium ions to pass through and their function is they open and close in response to changes in membrane.
Likewise, what happens if voltage gated sodium channels are blocked? For example, if the voltage gated Na + channel is blocked, the cell will not be able to depolarize and the action potential will not be generated. By simply adding 120 mM K + to the extracellular fluid, the cell would depolarize without an action potential.
People also ask, what are voltage gated sodium channels made of?
Voltage-gated sodium channels normally consist of an alpha subunit that forms the ion conduction pore and one to two beta subunits that have several functions including modulation of channel gating. Expression of the alpha subunit alone is sufficient to produce a functional channel.
What causes voltage gated ion channels to open?
Voltage-gated channels open when the transmembrane voltage changes around them. Amino acids in the structure of the protein are sensitive to charge and cause the pore to open to the selected ion.
Genetics of Epilepsy
Ortrud K. Steinlein , in Progress in Brain Research , 2014
Voltage-gated sodium channels have a crucial role with regard to neuronal function. They control the sodium exchange between the extracellular and intracellular spaces, and are essential for the initiation and firing of action potentials ( Hu et al., 2009 ). Their important role in neuronal excitability renders them prime candidates for episodic neurological disorders such as epilepsy. It is therefore not surprising that mutations in various voltage-gated sodium channel subtypes have been found to cause different forms of epileptic disorders, and that such mutations are recognized as one of the most important causes of genetic epilepsy ( Mulley et al., 2005 ). The seizure phenotypes caused by voltage-gated sodium channel mutations are heterogeneous and range from benign to severe if not even devastating, reflecting the importance of this ion channel superfamily for the regulation of cellular excitability on several functional levels ( Table 1 ). Typical examples for the clinical phenotypes caused by voltage-gated sodium channel mutations are benign familial neonatal–infantile seizures and the severe and sometimes fatal Dravet syndrome (also known as severe myoclonic epilepsy of infancy (SMEI)) ( Baulac et al., 1999 Escayg et al., 2000 Heron et al., 2010 Kaplan and Lacey, 1983 Marini et al., 2011 Meisler and Kearney, 2005 Reid et al., 2009 ). These two epilepsy syndromes represent the extreme ends of the spectrum of clinical severity, while a third one, genetic epilepsy with febrile seizures plus (GEFS + ), presents with a more intermediate phenotype that can include both benign and severe manifestations ( Baulac et al., 1999 Escayg et al., 2000 Scheffer and Berkovic, 1997 Scheffer et al., 2009 ) ( Table 1 ).
Table 1 . Epilepsy phenotypes caused by voltage-gated sodium channel mutations
|Subunit class||Gene||Channel subunit||Epilepsy phenotypes a|
West syndrome (infantile spasms)
Doose syndrome (myoclonic astatic epilepsy)
Intractable childhood epilepsy with generalized tonic–clonic seizures (ICEGTC)
Rasmussens's encephalitis Lennox–Gastaut syndrome
|SCN2A||Nav1.2||Benign familial neonatal–infantile seizures|
Early infantile epileptic encephalopathy
Benign familial infantile seizure
|SCN8A||Nav1.6||Infantile epileptic encephalopathy|
Structure of VGSC
Voltage-gated sodium channels are heteromeric integral membrane glycoproteins that can be differentiated by their primary structure, kinetics, and relative sensitivity to the neurotoxin tetrodotoxin (TTX). They are composed of an α-subunit of approximately 260 kDa ( amino acids), that is associated with one or more regulatory β-subunits (㬡–㬤) of approximately 35 kDa each (Catterall, 2000). We will describe in detail both subunits (α and β) that conform the VGSC.
Ten different mammalian α-subunit isoforms (NaV1.1–NaV1.9 and NaX) have been characterized (Table 1) and at least seven of them are expressed in the nervous system. NaV1.1, NaV1.2, NaV1.3, and NaV1.6 isoforms are mainly expressed in the central nervous system (CNS). In contrast, NaV1.7, NaV1.8, and NaV1.9 isoforms are predominantly located in the peripheral nervous system (PNS Ogata and Ohishi, 2002), are known to accumulate in the region of peripheral nerve injury and may be important in chronic, neuropathic pain (Devor, 2006 Table 1). In recent reports SCN10A/NaV1.8 has also been identified in human hearts (Facer et al., 2011 Yang et al., 2012) and in intracardiac neurons (Verkerk et al., 2012), where genetic variations in the SCN10A gene have been associated with alterations in the PR interval, QRS duration, and ventricular conduction (Chambers et al., 2010 Sotoodehnia et al., 2010). Because these isoforms (NaV1.1𠄱.3, NaV1.6𠄱.9) are mainly localized in nervous tissue they are generally referred as “brain type” or “neuronal-type” sodium channels. NaV1.4 isoform is mainly expressed in skeletal muscle, while NaV1.5 is the cardiac-specific isoform. The isoform referred to as “NaX channel” [also named NaG/SCL11 (rats), Nav2.3 (mice), and/or hNav2.1 (humans)] identifies a subfamily of sodium channel-like proteins (George et al., 1992). This channel has significant differences in the amino acid sequence in the voltage sensor, inactivation gate, and pore region when compared to the rest of VGSC (George et al., 1992 Goldin et al., 2000). NaX is normally expressed in a variety of organs including the heart, skeletal muscle, uterus, dorsal root ganglia (DRG), and brain [mainly in the circumventricular organs (CVOs)]. The difficulties in the characterization of the biophysical properties of this channel are mainly due to lack of success in expressing the functional protein in heterologous expression systems. Hiyama et al. (2002) generated a mouse model in which the NaX gene was knocked out. This group confirmed that Nax channel was expressed in neurons in the CVOs that play a fundamental role controlling body fluid and ionic balance. This group reported that under thirst conditions, mice lacking Nax showed hyperactivity of the neurons in these areas and ingested excessive salt, while wild-type mice did not. This led the investigators to propose that NaX was involved in the mechanism that senses sodium levels in the brain, where this protein might sense extracellular sodium concentration (Hiyama et al., 2002 Noda, 2006).
Table 1. Summary of the different types of VGSC, and the channelopathies associated to mutations in the genes encoding the α subunits.
Each α-subunit is arranged in four homologous domains (DI𠄽IV) that contain six transmembrane segments (S1–S6 Figure 1). Using cryo-electron microscopy Sato et al. (2001) showed that these four domains are arranged around the central pore of the channel. Segment 4 of each domain contains a high concentration of positive charges (mostly arginine) and functions as the core of the voltage sensor responsible for the voltage-dependent activation of the channels. Segment 6 from all four domains forms the inner surface of the pore. The hairpin-like loop between segments 5 and 6 [S5–S6 hairpin-like P(ore)-loop] is part of the pore of the channel and forms a narrow (ion-selective) filter that controls the ion selectivity and permeation at the extracellular side of the pore (Catterall, 2000 Yu and Catterall, 2003 George, 2005).
Payandeh et al. (2011) recently reported the crystal structure of NaVAb, a VGSC found in the bacterium Arcobacter butzleri. NaVAb is part of the NachBac channel family, which is a well-established model to study vertebrate NaV and CaV channels (Ren et al., 2001 Koishi et al., 2004 Payandeh et al., 2011). Payandeh et al. (2011) were able to capture this channel in the close configuration when the pore was closed with four activated voltage sensors at a resolution limit of 2.7 Å. Payandeh’s work provides the first insight into the structural basis for voltage-dependent gating ion selectivity and drug block in VGSC. The pore consists of an outer tubular vestibule, a selectivity filter, a central cavity (which can lodge partially hydrated sodium ions) and an intracellular activation gate. The helices that constitute the pore are positioned to stabilize cations in the central cavity through helical-dipole interactions (Doyle et al., 1998 Jogini and Roux, 2005). A second P2-helix forms an extracellular funnel and represents a highly conserved element in sodium channels (Payandeh et al., 2011).
Payandeh and coworkers proposed that in NaVAb the ion conduction pathway is electronegative and the selectivity filter (mainly composed of negatively charged glutamate (Glu) side chains) forms the narrowest constriction near the extracellular side of the membrane. There are 4 Glu 177 side chains that form a 6.5-Å × 6.5-Å scaffold with an orifice of approximately 4.6 Å wide. A profuse mesh of amino acid residue interactions, including hydrogen bonds between glutamine from the P-helix and the carbonyl of Glu, stabilizes the selectivity filter. The radius of the pore suggests that hydrated Na + ions can conduct through the channel. Free diffusion then allows the hydrated Na + to enter the central cavity and move through the open activation gate toward the cytoplasm (Payandeh et al., 2011). This permeation pathway contrasts with the selectivity filter in K + channels, which is much narrower. In this case the smaller radius of the pore can only conduct dehydrated K + ions through direct interactions with backbone carbonyls through a long, narrow pore (Morais-Cabral et al., 2001 Ye et al., 2010).
Identification of the primary structure of VGSC led to the development of the “sliding helix” (Catterall, 1986b) and the “helical screw” (Guy and Seetharamulu, 1986) models (validated by structure-function studies) to better understand how the voltage sensor operates. Both models suggest that positively charged residues in segment 4 within each domain serve as the gating charges moving outward across the membrane as a consequence of membrane depolarization, initiating the activation process (Catterall, 1986a,b Guy and Seetharamulu, 1986 Catterall et al., 2010). Catterall and coworkers have extensively described these two models. Basically, four to seven residues positively charged within segment 4 would pair negatively charged residues in segments 1, 2, and/or 3. In this configuration, positively charged residues in segment 4 are pulled inward by the electric field of the resting membrane potential which is negative. As depolarization progresses, the change in the polarity of the membrane potential relieve the electrostatic force and the segments 4 move outward allowing each positive charged amino acid in the segment 4 pairs a negatively charged one. As described by Catterall (2010), this outward movement of the gating charges in segments 4 pulls the linker between segments 4 and 5, curves the segment 6 and initiates the opening of the central pore of the channel. The movement of charged particles to activate the sodium conductance (“gating charges” or “gating current”) was first predicted by Hodgkin and Huxley(Hodgkin and Huxley, 1952 Catterall, 2010), but Armstrong and Bezanilla (1973) were the first ones that measured it in 1973, combining the techniques of internal perfusion, voltage-clamp, and signal average. Using similar techniques, Keynes and Rojas (1973) confirmed the existence of the gating current the same year. Armstrong and Bezanilla (1974) reported additional properties of this current and strong evidence linking it to the gating of the sodium channels the following year.
Figure 1. Schematic representation of the α- and β-subunits of the VGSC. The four homologous domains (I–IV) of the α-subunit are represented S5 and S6 are the pore-lining segments and S4 is the core of the voltage sensor. In the cytoplasmic linker between domains III and IV the IFMT (isoleucine, phenylalanine, methionine, and threonine) region is indicated. This is a critical part of the “inactivation particle” (inactivation gate), and substitution of aminoacids in this region can disrupt the inactivation process of the channel. The 𠇍ocking site” consists of multiple regions that include the cytoplasmic linker between S4–S5 in domains III and IV, and the cytoplasmic end of the S6 segment in domain IV (*). Depending on the subtype of β-subunit considered they could interact (covalently or non-covalently) with the α-subunit.
These are integral proteins as well, composed of one extracellular domain (ECD, N-terminal domain), one transmembrane domain, and one intracellular domain (C-terminal domain). The β-subunits are expressed in excitable and non-excitable cells within the nervous system and the heart, and there is some evidence suggesting that these proteins can be expressed in the cells even in the absence of the α-subunit (Patino and Isom, 2010 Table 2). One or more regulatory β-subunits (㬡–㬤) can associate with one α-subunit. An individual α-subunit can be associated with one non-covalently (㬡 or 㬣) and one covalently (㬢 or 㬤) linked β-subunits (Yu and Catterall, 2003 Catterall et al., 2005 Patino and Isom, 2010). The role of β-subunits has been reviewed in detail by Patino and Isom (2010). The authors remark that β-subunits are regulatory proteins that can act both as cell adhesion molecules (CAMs) and modulate the cell surface expression of the VGSC, enhancing sodium channel density and cell excitability. The latter may be a very important mechanism that regulates nociceptor excitability in vivo (Lopez-Santiago et al., 2011). 㬡 association with contactin or neurofascin (NF)-186 also results in increased VGSC cell surface expression (Kazarinova-Noyes et al., 2001 McEwen and Isom, 2004). Furthermore, 㬡 and 㬢 are ankyrin-binding proteins. Mice lacking ankyrin exhibit reduced sodium current (INa) density and abnormal INa kinetics (Chauhan et al., 2000), suggesting that β-subunits play important roles in the VGSC𠄺nkyrin complex (Patino and Isom, 2010). The interaction between α- and β-subunits may be particularly critical at the nodes of Ranvier of myelinated axons, since mice lacking 㬡-subunit have reduced numbers of nodes, alterations in the myelination process, and drastically altered contacts between neurons and glial cells (Chen et al., 2004). Even though proteins within nodal regions are localized normally in these mice, association between VGSC and contactin is disrupted. Loss of 㬡-subunit dependent protein–protein interactions can lead to changes in the structure of the Ranvier nodes and disrupted saltatory conduction (Chen et al., 2004 Davis et al., 2004). Similar to the 㬡- subunit, 㬢 can also modulate the expression of the channel at the cell surface and affect INa density (Isom et al., 1995). 㬢 (and 㬤) intracellular domains can translocate into the nucleus and enhance SCN1A expression, thus functioning as transcriptional regulators of the VGSC α-subunit.
β-subunits are also critical for cellular migration. 㬡 and 㬢 mediate migration of fibroblasts (Xiao et al., 1999) and cancer cells (Brackenbury and Isom, 2008), adhesion, and neurite outgrowth (㬡 promotes and 㬢 inhibits this process, while 㬣 and 4 have no effect Davis et al., 2004 McEwen et al., 2009). The effects of β-subunits on cell migration, adhesion, and neurite outgrowth also depends on intracellular transduction events like the activation of proto-oncogene tyrosine-protein kinase fyn by 㬡 to promote neurite (axon and/or dendrite) outgrowth (Brackenbury et al., 2008).
Table 2. Summary of the different types of β subunits associated with the different VGSC, and the related channelopathies associated with the mutations in the genes that encode them (modified from Patino and Isom, 2010).
Changes of the biophysical properties of voltage-gated Na + currents during maturation of the sodium-taste cells in rat fungiform papillae
Taste cells are a heterogeneous population of sensory receptors that undergoes a continuous turnover. Different chemo-sensitive cell lines rely on action potentials to release the neurotransmitter onto nerve endings. The electrical excitability is due to the presence of a tetrodotoxin-sensitive, voltage-gated sodium current (INa) similar to that found in neurons. Since the biophysical properties of INa change during neuronal development, we wondered whether the same also occurred in taste cells. Here, we used the patch-clamp recording technique to study INa in sodium sensing cells of rat fungiform papillae. We identified these cells by exploiting the known blocking effect of amiloride on ENaC, the sodium (salt) receptor. Then, based on the amplitude of INa and a morphological analysis, we subdivided sodium cells into two broad developmental groups, namely immature and mature cells. We found that: the voltage dependence of activation and inactivation changed in the transition from immature to mature state (depolarizing shift) the membrane capacitance significantly decreased in mature cells, enhancing the density of INa a persistent sodium current, absent in immature cells, appeared in mature cells. mRNA expression analysis of the α-subunits of voltage-gated sodium channels in fungiform taste buds supported the electrophysiological data. As a whole, our findings provide evidence for a noticeable change in membrane excitability during development, which is consistent with the key role played by electrical signaling in the release of neurotransmitter by mature sodium cells.
Key Points Summary
Taste cells are sensory receptors that undergo continuous turnover while they detect food chemicals and communicate with afferent nerve fibers.
The voltage-gated sodium current (INa) is a key ion current for generating action potentials in fully differentiated and chemo-sensitive taste cells, which use electrical signaling to release neurotransmitters.
Here we report that in rat taste cells involved in salt detection, the properties of INa, such as voltage dependence of activation and inactivation, undergo significant changes during the transition from immature to mature state.
Our results help understand how taste cells gain electrical excitability during turnover, a property critical to operate as chemical detectors that relay sensory information to nerve fibers.
Inherited disorders of voltage-gated sodium channels
Division of Genetic Medicine, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
Address correspondence to: Alfred L. George Jr., Division of Genetic Medicine, 529 Light Hall, Vanderbilt University, Nashville, Tennessee 37232-0275, USA. Phone: (615) 936-2660 Fax: (615) 936-2661 E-mail: [email protected]
A variety of inherited human disorders affecting skeletal muscle contraction, heart rhythm, and nervous system function have been traced to mutations in genes encoding voltage-gated sodium channels. Clinical severity among these conditions ranges from mild or even latent disease to life-threatening or incapacitating conditions. The sodium channelopathies were among the first recognized ion channel diseases and continue to attract widespread clinical and scientific interest. An expanding knowledge base has substantially advanced our understanding of structure-function and genotype-phenotype relationships for voltage-gated sodium channels and provided new insights into the pathophysiological basis for common diseases such as cardiac arrhythmias and epilepsy.
Voltage-gated sodium channels (NaVChs) are important for the generation and propagation of signals in electrically excitable tissues like muscle, the heart, and nerve. Activation of NaVChs in these tissues causes the initial upstroke of the compound action potential, which in turn triggers other physiological events leading to muscular contraction and neuronal firing. NaVChs are also important targets for local anesthetics, anticonvulsants, and antiarrhythmic agents.
The essential nature of NaVChs is emphasized by the existence of inherited disorders (sodium “channelopathies”) caused by mutations in genes that encode these vital proteins. Nearly 20 disorders affecting skeletal muscle contraction, cardiac rhythm, or neuronal function and ranging in severity from mild or latent disease to life-threatening or incapacitating conditions have been linked to mutations in human NaVCh genes (Table 1). Most sodium channelopathies are dominantly inherited, but some are transmitted by recessive inheritance or appear sporadic. Additionally, certain pharmacogenetic syndromes have been traced to variants in NaVCh genes. The clinical manifestations of these disorders depend primarily on the expression pattern of the mutant gene at the tissue level and the biophysical character of NaVCh dysfunction at the molecular level.
Inherited disorders of NaVChs
This review will cover the current state of knowledge of human sodium channelopathies and illustrate important links among clinical, genetic, and pathophysiological features of the major syndromes with the corresponding biophysical properties of mutant NaVChs. An initial brief overview of the structure and function of NaVChs will provide essential background information needed to understand the nuances of these relationships. This will be followed by a review of the major syndromes, organized by affected tissue. Emphasis will be placed on relating clinical phenotypes to patterns of channel dysfunction that underlie pathophysiology of these conditions.
Sodium channels are heteromultimeric, integral membrane proteins belonging to a superfamily of ion channels that are gated (opened and closed) by changes in membrane potential ( 1 , 2 ). Sodium channel proteins from mammalian brain, muscle, and myocardium consist of a single large (approximately 260 kDa) pore-forming α subunit complexed with 1 or 2 smaller accessory β subunits (Figure 1). Nine genes (SCN1A, SCN2A, etc.) encoding distinct α subunit isoforms and 4 β subunit genes (SCN1B, SCN2B, etc.) have been identified in the human genome. Many isoforms are expressed in the central and peripheral nervous system ( 3 ), while skeletal muscle and cardiac muscle express more restricted NaVCh repertoires ( 4 – 9 ). The α subunits are constructed with a 4-fold symmetry consisting of structurally homologous domains (D1–D4) each containing 6 membrane-spanning segments (S1–S6) and a region (S5–S6 pore loop) controlling ion selectivity and permeation (Figure 1). The S4 segment, which functions as a voltage sensor ( 10 , 11 ), is amphipathic with multiple basic amino acids (arginine or lysine) at every third position surrounded by hydrophobic residues. Each domain resembles an entire voltage-gated potassium channel subunit as well as a primitive bacterial NaVCh ( 12 ).
Structure and genomic location of human NaVChs. (A) Simple model representing transmembrane topology of α and β NaVCh subunits. Structural domains mediating key functional properties are labeled. (B) Chromosomal location of human genes encoding α (red) and β (blue) subunits across the genome. An asterisk next to the gene name indicates association with an inherited human disease. A double asterisk indicates association with murine phenotypes.
NaVChs switch between 3 functional states depending on the membrane potential (Figure 2) ( 13 ). In excitable membranes, a sudden membrane depolarization causes a rapid rise in local Na + permeability due to the opening (activation) of NaVChs from their resting closed state. For this to occur, voltage sensors (the 4 S4 segments) within the NaVCh protein must move in an outward direction, propelled by the change in membrane potential, and then translate this conformational energy to other structures (most likely S6 segments) that swing out of the way of incoming Na + ions. This increase in Na + permeability causes the sudden membrane depolarization that characterizes the initial phase of an action potential. Normally, activation of NaVChs is transient owing to inactivation, another gating process mediated by structures located on the cytoplasmic face of the channel protein (mainly the D3–D4 linker). NaVChs cannot reopen until the membrane is repolarized and they undergo recovery from inactivation. Membrane repolarization is achieved by fast inactivation of NaVChs and is augmented by activation of voltage-gated potassium channels. During recovery from inactivation, NaVChs may undergo deactivation, the transition from the open to the closed state ( 14 ). Activation, inactivation, and recovery from inactivation occur within a few milliseconds. In addition to these rapid gating transitions, NaVChs are also susceptible to closing by slower inactivating processes (slow inactivation) if the membrane remains depolarized for a longer time ( 15 ). These slower events may contribute to determining the availability of active channels under various physiological conditions.
Functional properties of NaVChs. (A) Schematic representation of an NaVCh undergoing the major gating transitions. (B) Voltage-clamp recording of NaVCh activity in response to membrane depolarization. Downward deflection of the current trace (red) corresponds to inward movement of Na + .
Disturbances in the function of muscle NaVChs can affect the ability of skeletal muscle to contract or relax. Two symptoms are characteristic of muscle membrane (sarcolemma) NaVCh dysfunction, myotonia and periodic paralysis ( 16 ). Myotonia is characterized by delayed relaxation of muscle following a sudden forceful contraction and is associated with repetitive action potential generation, a manifestation of sarcolemmal hyperexcitability. By contrast, periodic paralysis represents a transient state of hypoexcitability or inexcitability in which action potentials cannot be generated or propagated.
Periodic paralysis and myotonia. Periodic paralysis is characterized by episodic weakness or paralysis of voluntary muscles occurring with normal neuromuscular transmission and in the absence of motor neuron disease. Patients with familial periodic paralysis present typically in childhood ( 17 ). Attacks of weakness are often associated with changes in the serum potassium (K + ) concentration as a result of abrupt redistribution of intracellular and extracellular K + . This clinical epiphenomenon forms the basis for classifying periodic paralysis as hypokalemic, hyperkalemic, or normokalemic. In paramyotonia congenita, the dominant symptom is cold-induced muscle stiffness and weakness ( 17 , 18 ). Potassium-aggravated myotonia is characterized by myotonia without weakness and worsening symptoms following K + ingestion ( 19 ). In general, these disorders are not associated with disabling muscular dystrophy, although chronic weakness may develop in some individuals with long-standing hyperkalemic periodic paralysis ( 20 ).
In vitro electrophysiological studies determined that both myotonia and periodic paralysis are associated with abnormal muscle cell membrane sodium conductance ( 21 ), and these findings pointed to SCN4A as the most plausible candidate gene. Genetic linkage studies confirmed this hypothesis ( 22 – 24 ). Hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia are all associated with missense mutations in SCN4A. There are 2 predominant mutations associated with hyperkalemic periodic paralysis (T704M and M1592V), and these occur independently in unrelated kindreds ( 20 , 25 ). Allelic diversity is greater for paramyotonia congenita and potassium-aggravated myotonia ( 26 – 32 ). In addition, approximately 15% of patients with genotype-defined hypokalemic periodic paralysis carry SCN4A mutations ( 33 ). Patients with SCN4A mutations may present rarely with life-threatening myotonic reactions upon exposure to succinylcholine resembling the syndrome of malignant hyperthermia susceptibility ( 34 , 35 ). In 1 report, congenital myasthenia has been linked to SCN4A mutations ( 36 ).
Characterization of SCN4A mutations and pathophysiology. Using heterologously expressed recombinant NaVChs, several laboratories have characterized the biophysical properties of many mutations associated with either periodic paralysis or various myotonic disorders. These studies demonstrated that variable defects in the rate or extent of inactivation occur in virtually all cases. Mutations associated with hyperkalemic periodic paralysis exhibit incomplete inactivation leading to a small level (1–2% of peak current) of persistent Na + current that is predicted to cause sustained muscle fiber depolarization (Figure 3) ( 37 , 38 ). Sustained depolarization will cause the majority of NaVChs (mutant and wild type) to become inactivated, and this explains conduction failure and electrical inexcitability observed in skeletal muscle during an attack of periodic paralysis ( 39 , 40 ). By this mechanism, mutant NaVChs exert an indirect dominant-negative effect on normal channels. In addition, some, but not all, mutations associated with hyperkalemic periodic paralysis have impaired slow inactivation ( 41 ), and this may contribute to sustaining the effect of persistent Na + current ( 42 ).
A common form of defective inactivation exhibited by mutant NaVChs associated with hyperkalemic periodic paralysis, long QT syndrome, and inherited epilepsy. The defect is caused by incomplete closure of the inactivation gate (left panel) resulting in an increased level of persistent current (right panel, red trace) as compared with NaVChs with normal inactivation (black trace).
SCN4A mutations in the myotonic disorders slow the rate of inactivation, speed recovery from inactivation, and slow deactivation ( 30 , 43 – 47 ). These biophysical defects are predicted to lengthen the duration of muscle action potentials ( 48 ). Prolongation of action potentials along T-tubule membranes will exaggerate the local rise in extracellular K + concentration by efflux through persistently activated potassium channels. Extracellular K + in T-tubules exerts a depolarizing effect on the resting membrane potential, increasing the probability of an aberrant afterdepolarization. A large afterdepolarization can trigger spontaneous action potentials in adjacent surface membranes, which in turn cause persistent muscle contraction and delayed relaxation, the physiological hallmarks of myotonia (Figure 4) ( 49 ).
Differences between normal and myotonic muscle action potentials. (A) Generation of action potential spikes during electrical stimulation (horizontal blue line and square wave) of a normal muscle fiber. Contraction occurs during action potential firing, followed by muscle relaxation when stimulation ceases. (B) Action potentials in myotonic muscle during and immediately after electrical stimulation. An afterdepolarization triggers spontaneous action potentials that fire after termination of the electrical stimulus (myotonic activity).
Treatment strategies for muscle sodium channelopathies. Pharmacological treatment for periodic paralysis with carbonic anhydrase inhibitors is often successful, but the mechanism of action is poorly understood ( 50 , 51 ). Certain local anesthetic/antiarrhythmic agents have antimyotonic activity and are sometimes useful treatments for nondystrophic myotonias ( 52 , 53 ). These drugs are effective because of their ability to interrupt rapidly conducted trains of action potentials through their use-dependent NaVCh-blocking action. Mexiletine is the most commonly used antimyotonic agent, and there have been in vitro studies demonstrating its effectiveness ( 54 ), but there have been no clinical trials comparing this agent with either placebo or other treatments. A more potent NaVCh blocker, flecainide, may also have utility in severe forms of myotonia that are resistant to mexiletine ( 55 ). The efficacy of flecainide for treating myotonia associated with certain SCN4A mutations may be greatest when there is a depolarizing shift of the steady-state fast inactivation curve for the mutant channel, whereas mutations that induce hyperpolarizing shifts in this curve are predicted to have greater sensitivity to mexiletine ( 56 ). Long-term treatment of myotonia with NaVCh blockers is often limited by drug side effects.
In the heart, NaVChs are essential for the orderly progression of action potentials from the sinoatrial node, through the atria, across the atrioventricular node, along the specialized conduction system of the ventricles (His-Purkinje system), and ultimately throughout the myocardium to stimulate rhythmic contraction. Mutations in SCN5A, the gene encoding the principal NaVCh α subunit expressed in the human heart, cause inherited susceptibility to ventricular arrhythmia (congenital long QT syndrome, idiopathic ventricular fibrillation) ( 57 – 59 ), impaired cardiac conduction ( 60 ), or both ( 61 – 65 ). SCN5A mutations may also manifest as drug-induced arrhythmias ( 66 ), sudden infant death syndrome (SIDS) ( 67 , 68 ), and other forms of arrhythmia susceptibility ( 69 ).
Inherited arrhythmia syndromes: long QT and Brugada. Congenital long QT syndrome (LQTS), an inherited condition of abnormal myocardial repolarization, is characterized clinically by an increased risk of potentially fatal ventricular arrhythmias, especially torsade de pointes ( 70 , 71 ). The syndrome is transmitted most often in families as an autosomal dominant trait (Romano-Ward syndrome) and less commonly as an autosomal recessive disease combined with congenital deafness (Jervell and Lange-Nielsen syndrome). The syndrome derives its name from the characteristic prolongation of the QT interval on surface ECGs of affected individuals, a surrogate marker of an increased ventricular action potential duration and abnormal myocardial repolarization. Approximately 10% of LQTS cases are caused by SCN5A mutations, whereas the majority of Romano-Ward subjects harbor mutations in 2 cardiac potassium channel genes (KCNQ1 and HERG) ( 72 , 73 ). Triggering factors associated with arrhythmic events are different among genetic subsets of LQTS. SCN5A mutations often produce distinct clinical features including bradycardia, and a tendency for cardiac events to occur during sleep or rest ( 74 , 75 ).
Mutations in SCN5A have also been associated with idiopathic ventricular fibrillation, including Brugada syndrome ( 59 , 76 ) and sudden unexplained death syndrome (SUDS) ( 77 , 78 ). Individuals with Brugada syndrome have an increased risk for potentially lethal ventricular arrhythmias (polymorphic ventricular tachycardia or fibrillation) without concomitant ischemia, electrolyte abnormalities, or structural heart disease. Individuals with the disease often exhibit a characteristic ECG pattern consisting of ST elevation in the right precordial leads, apparent right bundle branch block, but normal QT intervals ( 79 ). Administration of NaVCh-blocking agents (i.e., procainamide, flecainide, ajmaline) may expose this ECG pattern in latent cases ( 80 ). Inheritance is autosomal dominant with incomplete penetrance and a male predominance. A family history of unexplained sudden death is typical. SUDS is a very similar syndrome that causes sudden death, typically during sleep, in young and middle-aged males in Southeast Asian countries ( 81 – 83 ).
Disorders of cardiac conduction. Mutations in SCN5A are also associated with heterogeneous familial disorders of cardiac conduction manifest as impaired atrioventricular conduction (heart block), slowed intramyocardial conduction velocity, or atrial inexcitability (atrial standstill) ( 60 , 62 , 84 , 85 ). The degree of impaired cardiac conduction may progress with advancing age and is generally not associated with prolongation of the QT interval or ECG changes consistent with Brugada syndrome. Heart block in these disorders is usually the result of conduction slowing in the His-Purkinje system. In most cases, inheritance of the phenotype is autosomal dominant. By contrast, atrial standstill has been reported to occur either as a recessive disorder of SCN5A (congenital sick sinus syndrome) ( 85 ) or by digenic inheritance of a heterozygous SCN5A mutation with a promoter variant in the connexin-40 gene ( 84 ).
Mutations in SCN5A may also cause more complex phenotypes representing combinations of LQTS, Brugada syndrome, and conduction system disease. There have been documented examples of LQTS combined with Brugada syndrome ( 63 ) or congenital heart block ( 86 , 87 ), and cases of Brugada syndrome with impaired conduction ( 88 ). In 1 unique family, all 3 clinical phenotypes occur together ( 65 ). SCN5A mutations have also been discovered in families segregating impaired cardiac conduction, supraventricular arrhythmia, and dilated cardiomyopathy ( 64 , 89 ). Certain mutations may manifest different phenotypes in different families.
Characterization of SCN5A mutations and arrhythmogenesis. The clinical heterogeneity associated with SCN5A mutations is partly explained by corresponding differences in the degree and characteristics of channel dysfunction. In congenital LQTS, SCN5A mutations have a dominant gain-of-function phenotype at the molecular level. Specifically, most mutant cardiac NaVChs associated with LQTS exhibit a characteristic impairment of inactivation, leading to persistent inward Na + current during prolonged membrane depolarizations (Figure 3) ( 90 – 92 ). A general slowing of inactivation may be present in mutations associated with severe LQTS ( 93 ), while some mutations alter voltage-dependence of activation and inactivation but do not have measurable non-inactivating current ( 94 ). Persistent Na + current during the cardiac action potential explains abnormal myocardial repolarization in LQTS ( 95 ). By contrast with nerve and muscle, cardiac action potentials last several hundred milliseconds because of a prolonged depolarization phase (plateau), the result of opposing inward (mainly Na + and Ca 2+ ) and outward (K + ) ionic currents. Repolarization occurs when net outward current exceeds net inward current. Non-inactivating behavior of mutant cardiac NaVChs will shift this balance toward inward current and delay onset of repolarization, thus lengthening the action potential duration and the corresponding QT interval (Figure 5). Delayed repolarization predisposes to ventricular arrhythmias by exaggerating the dispersion of refractoriness throughout the myocardium and increasing the probability of early afterdepolarization, a phenomenon caused largely by reactivation of calcium channels during the action potential plateau ( 96 ). Both of these phenomena create conditions that allow electrical signals from depolarized regions of the heart to prematurely re-excite adjacent myocardium that has already repolarized, the basis for a reentrant arrhythmia. Additional proof of the role of cardiac NaVCh mutations in LQTS has come from studies of mice heterozygous for a prototypic LQTS SCN5A mutation (delKPQ). These mice have spontaneous life-threatening ventricular arrhythmias and a persistent Na + current in cardiac myocytes ( 97 ). SCN5A mutations associated with SIDS also exhibit this biophysical phenotype this suggests a pathophysiological relationship with LQTS ( 67 , 68 ).
Electrophysiological basis for LQTS. (A) Relationship of surface ECG (top) with a representative cardiac action potential (bottom). The QT interval approximates the action potential duration. Individual ionic currents responsible for different phases of the action potential are labeled. (B) Prolongation of the QT interval and corresponding abnormal cardiac action potential (blue) resulting from persistent sodium current. ICa, calcium current IK1, inward rectifier current IKr, rapid component of delayed rectifier current IKs, slow component of delayed rectifier current INa, sodium current ITO, transient outward current.
The proposed cellular basis of Brugada syndrome involves a primary reduction in myocardial sodium current that exaggerates differences in action potential duration between the inner (endocardium) and outer (epicardium) layers of ventricular muscle ( 96 , 98 , 99 ). These differences exist initially because of an unequal distribution of potassium channels responsible for the transient outward current (ITO), a repolarizing current more prominent in the epicardial layer that contributes to the characteristic spike and dome shape of the cardiac action potential. Reduced myocardial Na + current will cause disproportionate shortening of epicardial action potentials because of unopposed ITO, leading to an exaggerated transmural voltage gradient, dispersion of repolarization, and a substrate promoting reentrant arrhythmias (Figure 6). This hypothesis has been validated using animal models and computational methods. The theory helps explain the characteristic ECG pattern observed in Brugada syndrome and the effects of NaVCh-blocking agents to aggravate the phenotype.
Electrophysiological basis for Brugada syndrome. (A) Comparison of endocardial and epicardial action potentials in normal heart. The epicardial action potential is shorter because of large transient outward current. (B) Endocardial and epicardial action potentials in Brugada syndrome. Reduced sodium current causes disproportionate shortening of epicardial action potentials with resulting exaggeration of the transmural voltage gradient (horizontal double arrow).
Consistent with reduced sodium current as the primary pathophysiological event in Brugada syndrome, many SCN5A mutations associated with this disease cause frameshift errors, splice site defects, or premature stop codons ( 59 , 100 ) that are predicted to produce nonfunctional channels. Furthermore, some missense mutations have also been demonstrated to be nonfunctional because of either impaired protein trafficking to the cell membrane or presumed disruption of Na + conductance through the channel ( 101 – 104 ). However, other missense mutations associated with Brugada syndrome are functional but have biophysical defects predicted to reduce channel availability, such as altered voltage-dependence of activation, more rapid fast inactivation, and enhanced slow inactivation ( 105 – 107 ).
Pathophysiology of SCN5A dysfunction in cardiac conduction disorders. Defects in cardiac NaVCh function due to mutations associated with disorders of cardiac conduction exhibit more complex biophysical properties ( 61 , 62 ). Mutations causing isolated conduction defects have generally been observed to cause reduced NaVCh availability as a consequence of mixed gating disturbances. In the case of a Dutch family segregating a specific missense allele (G514C), the mutation causes unequal depolarizing shifts in the voltage-dependence of activation and inactivation such that a smaller number of channels are activated at typical threshold voltages ( 61 ). Computational modeling of these changes supports reduced conduction velocity, but the level of predicted NaVCh loss is insufficient to cause shortened epicardial action potentials, which explains why these individuals do not manifest Brugada syndrome. Two other SCN5A mutations causing isolated conduction disturbances (G298S and D1595N) are also predicted to reduce channel availability by enhancing the tendency of channels to undergo slow inactivation in combination with a complex mix of gain- and loss-of-function defects ( 62 ). However, other alleles exhibiting complete loss of function have also been associated with isolated cardiac conduction disease ( 108 , 109 ) without the Brugada syndrome. These observations suggest that additional host factors may contribute to determining whether a mutation will manifest as arrhythmia susceptibility or impaired conduction. This idea is supported by the observation that a single SCN5A mutation causes either Brugada syndrome or isolated conduction defects in different members of a large French family ( 88 ).
Biophysical properties of mutant cardiac NaVChs associated with combined phenotypes are also more complex. An in-frame insertion mutation (1795insD) has been identified in a family segregating both LQTS and Brugada syndrome ( 63 ). This mutation causes an inactivation defect resulting in persistent Na + current characteristic of most other SCN5A mutations associated with LQTS, but it also confers enhanced slow inactivation with reduced channel availability that is more characteristic of Brugada syndrome ( 63 ). The 2 biophysical abnormalities are predicted to predispose to ventricular arrhythmia at extremes of heart rate by different mechanisms ( 110 ). Whereas persistent current will prolong the QT interval to a greater degree at slow heart rates, enhanced slow inactivation predisposes myocardial cells to activity-dependent loss of NaVCh availability at fast rates. In another unusual case, deletion of lysine-1500 in SCN5A was associated with the unique combination of LQTS, Brugada syndrome, and impaired conduction in the same family ( 65 ). The mutation impairs inactivation, resulting in a persistent Na + current, and reduces NaVCh availability by opposing shifts in voltage-dependence of inactivation and activation.
Unlike LQTS, Brugada syndrome, and isolated cardiac conduction disease, in which affected individuals are heterozygous for single NaVCh mutations, there are cases in which individuals with severe impairments in cardiac conduction have inherited mutations from both parents. Lupoglazoff et al. described a child homozygous for a missense SCN5A allele (V1777M) who exhibited LQTS with rate-dependent atrioventricular conduction block ( 86 ). In a separate report, probands from 3 families exhibited perinatal sinus bradycardia progressing to atrial standstill (congenital sick sinus syndrome) and were found to have compound heterozygosity for mutations in SCN5A ( 85 ). Compound heterozygosity in SCN5A has also been observed in 2 infants with neonatal wide complex tachycardia and a generalized cardiac conduction defect ( 111 ). In each case of compound heterozygosity, individuals inherited 1 nonfunctional or severely dysfunctional mutation from 1 parent and a second allele with mild biophysical defects from the other parent. Interestingly, the parents who were carriers of single mutations were asymptomatic, which suggests that they had subclinical disease or other host factors affording protection. These unusually severe examples of SCN5A-linked cardiac conduction disorders illustrate the clinical consequence of nearly complete loss of NaVCh function. Complete absence of the murine Scn5a locus results in embryonic lethality ( 112 ), and it is likely that homozygous deletion or inactivation of human SCN5A is also not compatible with life.
Treatment strategies for cardiac sodium channelopathies. Specific therapeutic options for SCN5A-linked disorders are limited. β-Adrenergic blockers remain the first line of therapy in LQTS albeit this treatment strategy may be less efficacious in the setting of SCN5A mutations ( 113 ). Clinical and in vitro evidence suggests that mexiletine may counteract the aberrant persistent Na + current and shorten the QT interval ( 114 , 115 ) in SCN5A mutation carriers, although there are no data indicating an improvement in mortality. Mexiletine has also been demonstrated to rescue trafficking defective SCN5A mutants in vitro ( 116 ). Flecainide has also been observed to shorten QT intervals in the setting of certain SCN5A mutations ( 117 , 118 ), but some have raised concern over the safety of this therapeutic strategy ( 119 ). Class III–type antiarrhythmic agents (quinidine, sotalol) may be beneficial in Brugada syndrome ( 120 , 121 ). Device therapy (implantable defibrillator for LQTS and Brugada syndrome pacemaker for conduction disorders) is also an important treatment option.
Neuronal NaVChs are critical for the generation and propagation of action potentials in the central and peripheral nervous system. Most of the 13 genes encoding NaVCh α or β subunits are expressed in the brain, peripheral nerves, or both ( 1 ). In addition to their critical physiological function, neuronal NaVChs serve as important pharmacological targets for anticonvulsants and local anesthetic agents ( 122 , 123 ). Their roles in genetic disorders including a variety of inherited epilepsy syndromes and a rare painful neuropathy have been revealed during the past 7 years.
Sodium channels and inherited epilepsies. Genetic defects in genes encoding 2 pore-forming α subunits (SCN1A and SCN2A) and the accessory β1 subunit (SCN1B) are responsible for a group of epilepsy syndromes with overlapping clinical characteristics but divergent clinical severity ( 124 – 129 ). Generalized epilepsy with febrile seizures plus (GEFS+) is usually a benignt disorder characterized by the frequent occurrence of febrile seizures in early childhood that persist beyond age 6 years, and epilepsy later in life associated with afebrile seizures with multiple clinical phenotypes (absence, myoclonic, atonic, myoclonic-astatic). Mutations in 3 neuronal NaVCh genes (SCN1A, SCN1B, and SCN2A) and a GABA receptor subunit (GABRG2) may independently cause GEFS+ or very similar disorders ( 130 , 131 ). Mutations in SCN2A have also been associated with benign familial neonatal-infantile seizures (BFNIS), a seizure disorder of infancy that remits by age 12 months with no long-term neurological sequelae ( 129 , 132 ). Interestingly, despite expression of SCN1A and SCN1B in the heart ( 9 ), there are no apparent cardiac manifestations associated with these disorders.
By contrast, severe myoclonic epilepsy of infancy (SMEI) and related syndromes have severe neurological sequelae. The diagnosis of SMEI is based on several clinical features, including (a) appearance of seizures, typically generalized tonic-clonic, during the first year of life, (b) impaired psychomotor development following onset of seizures, (c) occurrence of myoclonic seizures, (d) ataxia, and (e) poor response to antiepileptic drugs ( 133 ). Two designations, borderline SMEI (SMEB) ( 133 , 134 ) and intractable childhood epilepsy with frequent generalized tonic-clonic seizures (ICEGTC) ( 128 ), have been assigned to patients with a condition resembling SMEI but in whom myoclonic seizures are absent and less severe psychomotor impairment is evident. SCN1A mutations have been identified in probands affected by all of these conditions.
More than 100 SCN1A mutations have been identified, with missense mutations being most common in GEFS+ ( 125 , 135 – 139 ) and more deleterious alleles (nonsense, frameshift) representing the majority of SMEI mutations ( 126 , 140 , 141 ). Only missense mutations in SCN1A have been reported for patients diagnosed with either ICEGTC or SMEB. There are rare reports of families segregating both GEFS+ and either SMEI or ICEGTC ( 128 ). The overlapping phenotypes and molecular genetic etiologies among the SCN1A-linked epilepsies suggest that they represent a continuum of clinical disorders ( 142 ).
Sodium channel dysfunction and epileptogenesis. The first human NaVCh mutation associated with an inherited epilepsy (GEFS+) was discovered in SCN1B encoding the β1 accessory subunit ( 124 ). However, mutations in this gene have very rarely been associated with inherited epilepsy. Only 2 SCN1B mutations have been described to date, including a missense allele (C121W) and a 5–amino acid deletion (del70–74) ( 124 , 143 ). Both mutations occur in an extracellular Ig-fold domain of the β1 subunit that is important for functional modulation of NaVCh α subunits ( 144 , 145 ) and mediates protein-protein interactions critical for NaVCh subcellular localization in neurons ( 146 ). The C121W mutation disrupts a conserved disulfide bridge in this domain, and functional expression studies demonstrated a failure of the mutant to normally modulate the functional properties of recombinant brain NaVChs ( 124 , 147 ). These findings and the observed seizure disorder in mice with targeted deletion of murine β1 subunit indicate that SCN1B loss of function explains the epilepsy phenotype ( 148 ). Functional characterization of the SCN1B deletion allele has not been reported.
Expression studies of α subunit mutations have demonstrated a wide range of functional disturbances. Early findings indicated that SCN1A mutations causing GEFS+ promote a gain of function, while mutations associated with SMEI are predicted to disable channel function. Two studies have demonstrated that increased persistent Na + current is caused by several GEFS+ mutations ( 149 , 150 ). This behavior is reminiscent of the channel dysfunction associated with 2 other human sodium channelopathies discussed above, hyperkalemic periodic paralysis and LQTS (Figure 3). Non-inactivating Na + current may facilitate neuronal hyperexcitability by reducing the threshold for action potential firing. However, not all GEFS+ mutations exhibit increased persistent current. For example, a shift in the voltage-dependence of inactivation to more depolarized potentials has been observed for 2 other GEFS+ mutations (T875M and D1866Y). This functional change is predicted to increase channel availability at voltages near the resting membrane potential and is sufficient to enhance excitability in a simple computational model of a neuronal action potential ( 150 ). This may be an oversimplification, as T875M also exhibits enhanced slow inactivation, which is predicted to decrease channel availability. For D1866Y, the changed voltage-dependence of inactivation was attributed to decreased modulation by the β1 subunit, a novel epilepsy-associated mechanism. Other GEFS+ mutations have been described that are nonfunctional (V1353L, A1685V) or exhibit depolarizing shifts in voltage-dependence of activation (I1656M, R1657C) predicted to reduce channel activity ( 151 ). These findings indicate that more than 1 biophysical mechanism accounts for seizure susceptibility in GEFS+.
Most SCN1A mutations associated with SMEI are predicted to produce nonfunctional channels by introducing premature termination or frameshifts into the coding sequence. This observation led to the notion that SMEI stems from SCN1A haploinsufficiency. Consistent with this idea was the finding that some missense mutations associated with SMEI are nonfunctional ( 151 , 152 ). However, a simple dichotomy of gain versus loss of function to explain clinical differences between GEFS+ and SMEI is not consistent with recent observations. As mentioned above, some GEFS+ mutations exhibit loss-of-function characteristics. More recently, 2 SMEI missense alleles (R1648C and F1661S) were demonstrated to encode functional channels that exhibit a mixed pattern of biophysical defects consistent with either gain (persistent Na + current) or loss (reduced channel density, altered voltage-dependence of activation and inactivation) of function ( 152 ). The precise cellular mechanism by which this constellation of biophysical disturbances leads to epilepsy is uncertain and motivates further experiments in animal models to help determine the impact of NaVCh mutations.
SCN9A and painful inherited neuropathy. Mutations in another neuronal NaVCh gene, SCN9A, encoding an α subunit isoform expressed in sensory and sympathetic neurons, have been discovered in patients with familial primary erythermalgia, a rare autosomal dominant disorder characterized by recurrent episodes of severe pain, redness, and warmth in the distal extremities. Two missense SCN9A mutations were recently identified in Chinese patients ( 153 ). Both mutations cause a hyperpolarizing shift in the voltage-dependence of channel activation and slow the rate of deactivation ( 154 ). This combination of biophysical defects is predicted to confer hyperexcitability on peripheral sensory and sympathetic neurons, accounting for the episodic pain and vasomotor symptoms characteristic of the disease. Consistent with overactive NaVChs are anecdotal reports of improved symptoms during treatment with local anesthetic agents (i.e., lidocaine, bupivacaine) or mexiletine ( 155 – 157 ).
NaVChs are important from many perspectives. Their recognized importance in the physiology and pharmacology of nerve, muscle, and heart is now further emphasized by their role in inherited disorders affecting these tissues. The sodium channelopathies provide outstanding illustrations of the delicate balances that maintain normal operation of critical physiological events such as muscle contraction and conduction of electrical signals.
Despite the extensive array of disorders listed in Table 1, it is likely that other inherited or pharmacogenetic disorders are caused by mutations or polymorphisms in NaVCh genes. Only 6 of the 13 known genes encoding NaVCh subunits have been linked to human disease. However, spontaneous or engineered disruption of 2 other genes (Scn8a and Scn2b) causes neurological phenotypes in mice ( 158 – 160 ), suggesting that other human sodium channelopathies might exist. Establishing new genotype-phenotype relationships, exploring pathophysiology, and developing new treatment strategies remain exciting challenges for the future.
The author is supported by grants from the NIH (NS32387 and HL68880) and is the recipient of a Javits Neuroscience Award from the National Institute of Neurological Disorders and Stroke.
Nonstandard abbreviations used: GEFS+, generalized epilepsy with febrile seizures plus ICEGTC, intractable childhood epilepsy with frequent generalized tonic-clonic seizures LQTS, long QT syndrome NaVCh, voltage-gated sodium channel SIDS, sudden infant death syndrome SMEB, borderline severe myoclonic epilepsy of infancy SMEI, severe myoclonic epilepsy of infancy SUDS, sudden unexplained death syndrome.
Conflict of interest: The author has declared that no conflict of interest exists.
Control of excitability can occur at the genomic level by the regulation of transcription of channel genes. The expression of Na + channels is developmentally regulated and tissue restricted. Patterns of electrical activity can also feed back upon and influence transcription: for example, seizures alter Na + channel gene expression in the brain. Denervation induces the expression of the cardiac isoform of the channel in skeletal muscle, while transiently suppressing expression of the mature skeletal muscle isoform ( Kallen, Sheng, Yang, Chen, Rogart & Barchi, 1990 Yang, Sladky, Kallen & Barchi, 1991 ). Chronic exposure to antiarrhythmic drugs which block Na + channels can increase the steady-state levels of Na + channel mRNA, in a manner that would tend to counteract the effects of channel blockade ( Duff, Offord, West & Catterall, 1992 ).
The mechanisms controlling Na + channel gene expression are only just beginning to be understood. Expression of the brain type II Na + channel is restricted to neurons by a transcription silencer known as REST ( Chong et al. 1995 Eggen & Mandel, 1997 Tapia-Ramirez, Eggen, Peral-Rubio, Toledo-Aral & Mandel, 1997 ). REST is a transcription factor with C2H2 zinc finger motifs homologous to the Drosophila repressor Krüppel that binds to a specific silencer element (RE-1) in the promoter of the brain II channel. REST is found in most tissues its absence in neurons is what permits expression of the brain II isoform.
The Absolute Refractory Period:
Just after the neuron has generated an action potential, it cannot generate another one. Many sodium channels are inactive and will not open, no matter what voltage is applied to the membrane. Most potassium channels are open. This period is called the absolute refractory period. The neuron cannot generate an action potential because sodium cannot move in through inactive channels and because potassium continues to move out through open voltage-gated channels. A neuron cannot generate an action potential during the absolute refractory period.
Summary of Process
Nerve impulses consist of action potentials fired in neurons. Understanding the process of firing and recovering from an action potential is necessary to understanding nerve signaling. This summary divides the action potential into stages, found below. Follow the links below to the Glossary for questions about unknown terms.
Before the action potential:
- The neuron receives signals via its dendrites.
- Signals that fail to raise the potential to the threshold potential cause no change.
The start of the action potential:
- An incoming signal reaches threshold and opens the first set of voltage-gated sodium channels.
- Positively-charged sodium pours into the cell, causing depolarization.
(“Voltage-gated channels,” 2016)
- Depolarization in the first region causes the second set of sodium-channels to be depolarized to threshold.
The end of the action potential:
- The action potential reaches the axon terminal.
- This signals neurotransmitter to be launched into the synaptic cleft.
- The neurotransmitter diffuses across the gap to bind to receptor proteins on the next cell.
Recovering from the action potential:
- Once the neuron depolarizes to about +30 mV, the cell begins repolarization.
- Sodium channels close and potassium channels open.
- Positively-charged potassium leaves the cell, causing the potential to decrease.
- Sodium channels are inactivated during repolarization so an action potential can’t re-fire.
- The potassium exiting the cell will drive the membrane potential down to about -80 mV.
Returning to resting membrane potential:
- Sodium channels can now be reopened, but it is more difficult.
- A new signal must overcome the potential from threshold to resting plus the additional hyperpolarized potential.
- and natural diffusion bring the cell back to resting potential.
From the resting membrane potential, this process may repeat as the neuron receives new stimuli. To learn more about the process of beginning and transmitting a signal along a neuron, there is a video on the next tab and the Glossary of Terms contains more thorough definitions of the individual components described here. To test your knowledge of the nerve impulse, go to the Quiz tab.