Mutations In Nav1 Research Articles

Functional effects of drugs and toxins interacting with NaV1.4.

NaV1.4 is a voltage-gated sodium channel subtype that is predominantly expressed in skeletal muscle cells. It is essential for producing action potentials and stimulating muscle contraction, and mutations in NaV1.4 can cause various muscle disorders. The discovery of the cryo-EM structure of NaV1.4 in complex with β1 has opened new possibilities for designing drugs and toxins that target NaV1.4. In this review, we summarize the current understanding of channelopathies, the binding sites and functions of chemicals including medicine and toxins that interact with NaV1.4. These substances could be considered novel candidate compounds or tools to develop more potent and selective drugs targeting NaV1.4. Therefore, studying NaV1.4 pharmacology is both theoretically and practically meaningful.

Human pain channelopathies.

There has been significant progress in our understanding of the molecular basis by which nociceptors transduce and transmit noxious (tissue damaging) stimuli. This is dependent on ion channels, many of which are selectively expressed in nociceptors. Mutations in such proteins have recently been linked to inherited pain disorders in humans. An exemplar is the voltage-gated sodium channel (VGSC) NaV1.7. Loss of function mutations in NaV1.7 result in congenital inability to experience pain while gain-of-function mutations can cause a number of distinct neuropathic pain disorders, including erythromelalgia, paroxysmal extreme pain disorder, and small-fiber neuropathy. Furthermore, variants in the VGSCs 1.8 and 1.9 have also been linked to human pain disorders. There is a correlation between the impact of mutations on the biophysical properties of the ion channel and the severity of the clinical phenotype. Pain channelopathies are not restricted to VGSCs: a mutation in the ligand-gated ion channel TRPA1, (which responds to environmental irritants) causes a familial episodic pain disorder. Ion channel variants have also been linked to more common neuropathic pain disorders such as painful diabetic neuropathy. Not only do these ion channels present targets for novel analgesics, but stratification based on genotype may improve treatment selection of existing analgesics.

Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents.

Voltage-gated sodium channels (Nav) are key players in excitable tissues with the capability to generate and propagate action potentials. Mutations in the genes encoding Navs can lead to severe inherited diseases, and some of these so-called channelopathies show temperature-sensitive phenotypes, for example, paramyotonia congenita, Brugada syndrome, febrile seizure syndromes, and inherited pain syndromes like erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Nevertheless, most investigations of mutation-induced gating effects have been conducted at room temperature, and thus the role of cooling or warming in channelopathies remains poorly understood. Here, we investigated the temperature sensitivity of four Nav subtypes: Nav1.3, Nav1.5, Nav1.6, and Nav1.7, and two mutations in Nav1.7 causing IEM (Nav1.7/L823R) and PEPD (Nav1.7/I1461T) expressed in cells of the human embryonic kidney cell line using an automated patch clamp system. Our experiments at 15°C, 25°C, and 35°C revealed a shift of the voltage dependence of activation to more hyperpolarized potentials with increasing temperature for all investigated subtypes. Nav1.3 exhibited strongly slowed inactivation kinetics compared with the other subtypes that resulted in enhanced persistent current, especially at 15°C, indicating a possible role in cold-induced hyperexcitability. Impaired fast inactivation of Nav1.7/I1461T was significantly enhanced by a cooling temperature of 15°C. The subtype-specific modulation as well as the intensified mutation-induced gating changes stress the importance to consider temperature as a regulator for channel gating and its impact on cellular excitability as well as disease phenotypes.

Nav1.7 is essential for nociceptor action potentials in the mouse in a manner independent of endogenous opioids

Loss-of-function mutations in Nav1.7, a voltage-gated sodium channel, cause congenital insensitivity to pain (CIP) in humans, demonstrating that Nav1.7 is essential for the perception of pain. However, the mechanism by which loss of Nav1.7 results in insensitivity to pain is not entirely clear. It has been suggested that loss of Nav1.7 induces overexpression of enkephalin, an endogenous opioid receptor agonist, leading to opioid-dependent analgesia. Using behavioral pharmacology and single-cell RNA-seq analysis, we find that overexpression of enkephalin occurs only in cLTMR neurons, a subclass of sensory neurons involved in low-threshold touch detection, and that this overexpression does not play a role in the analgesia observed following genetic removal of Nav1.7. Furthermore, we demonstrate using laser speckle contrast imaging (LSCI) and invivo electrophysiology that Nav1.7 function is required for the initiation of C-fiber action potentials (APs), which explains the observed insensitivity to pain following genetic removal or inhibition of Nav1.7.

Scanning mutagenesis of the voltage-gated sodium channel NaV1.2 using base editing

It is challenging to apply traditional mutational scanning to voltage-gated sodium channels (NaVs) and functionally annotate the large number of coding variants in these genes. Using a cytosine base editor and a pooled viability assay, we screen a library of 368 guide RNAs (gRNAs) tiling NaV1.2 to identify more than 100 gRNAs that change NaV1.2 function. We sequence base edits made by a subset of these gRNAs to confirm specific variants that drive changes in channel function. Electrophysiological characterization of these channel variants validates the screen results and provides functional mechanisms of channel perturbation. Most of the changes caused by these gRNAs are classifiable as loss of function along with two missense mutations that lead to gain of function in NaV1.2 channels. This two-tiered strategy to functionally characterize ion channel protein variants at scale identifies a large set of loss-of-function mutations in NaV1.2.

Effects of mexiletine on a race-specific mutation in Nav1.5 associated with long QT syndrome.

Mutations in cardiac Nav1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Nav1.5 mutations vary across race-ethnic groups. The Nav1.5 mutation P1090L was linked with familial long QT syndrome (LQTS) and was identified as an ethnic-specific variant in Asians. To explore the role of the P1090L in the LQT syndrome, we characterized the effects of the mutation on the Nav1.5 channel function. We found that the P1090L mutation altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by the mutation. Mexiletine modified the recovery and development of inactivation of the mutation and reduced the mutated channel's availability. We characterized that the P1090L is a gain-of-function, the mutation presented a larger window current and increased channel availability. Treatment with mexiletine rescued the dysfunctional inactivation of the mutation. The results might potentially enable a mechanism-based approach to the treatment of LQTS.

Nav1.7 P610T mutation in two siblings with persistent ocular pain after corneal axon transection: impaired slow inactivation and hyperexcitable trigeminal neurons.

Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser-assisted in situ keratomileusis (LASIK). Although most patients do not experience postoperative pain, a small subgroup develop persistent ocular pain. We previously carried out genomic analysis and determined that some patients with persistent pain after axotomy of corneal axons during refractive surgery carry mutations in genes that encode the electrogenisome of trigeminal ganglion neurons, the ensemble of ion channels and receptors that regulate excitability within these cells, including SCN9A, which encodes sodium channel Nav1.7, a threshold channel abundantly expressed in sensory neurons that has been implicated in a number of pain-related disorders. Here, we describe the biophysical and electrophysiological profiling of the P610T Nav1.7 mutation found in two male siblings with persistent ocular pain after refractive surgery. Our results indicate that this mutation impairs the slow inactivation of Nav1.7. As expected from this proexcitatory change in channel function, we also demonstrate that this mutation produces increased spontaneous activity in trigeminal ganglion neurons. These findings suggest that this gain-of-function mutation in Nav1.7 may contribute to pain after injury to the axons of trigeminal ganglion neurons.NEW & NOTEWORTHY Mechanisms underlying pain after axonal injury remain elusive. A small subgroup of patients experience pain after corneal refractive surgery, providing a human pain model after well-defined injury to axons. Here we analyze a mutation (P610T) in Nav1.7, a threshold sodium channel expressed in nociceptors, found in two siblings with persistent ocular pain after refractive surgery. We show that it impairs channel slow inactivation, thereby triggering inappropriate repetitive activity in trigeminal ganglion axons that signal eye pain.

The role of Nav1.9 in the sensory perception of itch.

The somatosensory nervous system perceives and transfers sensory modalities such as pain and itch from the periphery to the sensory cortex. Pain continues to be extensively researched, whereas itch remains overlooked. An antagonistic relationship between the two has long been suggested and is becoming gradually more defined. Voltage-gated sodium channel (Nav) 1.9 has been implicated in pain-related syndromes. Three unrelated cases of congenital insensitivity to pain were reported to have a de novo heterozygous p.L811P gain-of-function mutation in Nav1.9 (SCN11A). Patients were also affected by severe pruritus. This suggests Nav1.9 as a key player in pruritic circuits. In this project we characterize Nav1.9-expressing neurons and assess its involvement in mouse chronic scratching behavior. To visualize Nav1.9 in the CNS through immunofluorescent imaging, a mouse line was created in which the channel is fused to superfolder GFP. Scratching behavior in wild-type and knock-out mice was observed upon triggering acute or chronic itch, respectively achieved through chloroquine injections and topical application of 1% squaric acid dibutylester (SADBE). Electrophysiological data was collected by performing the patch clamp technique on spinal cord slices of the sfGFP-tagged mouse line. Nav1.9 expression has been observed in the dorsal horn of the spinal cord and in various regions throughout the brain. Preliminary data of the SADBE itch assays show little to no response in KO mice, whereas WT mice develop chronic scratching behavior. Electrophysiological experiments are still ongoing and as of now inconclusive. We have uncovered expression in regions of the CNS that were previously undocumented. Electrophysiological data is needed to define and characterize the Nav1.9-expressing neurons. Preliminary behavioral data indicates a transmissive role for Nav1.9 in the sensory perception of itch, but more data is needed to establish these findings.

Enhancement of EFL-inactivation gate interaction by truncation of Nav1.5 carboxy-terminal domain.

The voltage-gated sodium channel 1.5 (NaV1.5) participates in the initiation of the cardiac action potential by undergoing rapid activation which, within milliseconds, is followed by inactivation. Human channelopathic mutations in NaV1.5 are linked to various cardiac maladies, including cardiac arrythmia, atrial fibrillation, and dilated cardiomyopathies. The carboxy-terminal domain (CTD) of NaV1.5 is a well-recognized hotspot for channelopathic mutations. This domain harbors an EF-hand-like domain (EFL) and an IQ motif, which tune channel function via binding of auxiliary proteins, including the fibroblast growth factor homologous factors and calmodulin. In addition, the isolated NaV1.5 EFL has been reported to bind the channel inactivation gate (IG) via a partially buried hydrophobic pocket. However, whether this binding occurs in the full-length human channel and how it tunes NaV1.5 function are not well understood. Here, we have used high-resolution multi-channel electrophysiology recordings of disease-associated truncations and engineered NaV1.5 mutants to probe this interaction. We show that truncation of the NaV1.5 CTD increases late Na current, with a maximal increase observed for a truncation that includes helix V of the EFL (NaV1.5E[1864]∗), while further truncation resulted in reduced late Na current. Deletion of helix V increases the exposure of the EFL hydrophobic pocket, suggesting the large late Na current observed for NaV1.5E[1864]∗ may stem from a tighter interaction between the IG and the mutant EFL. Consistent with this, co-expression of NaV1.5E[1864]∗ with the WT NaV1.5 CTD or IG reduced late Na current, while expression with IG mutants designed to disrupt binding with either the pore-domain (IFM/QQQ) or EFL (K1504E/K1505E) showed only a partial reduction. These findings suggest that as NaV1.5 cycles between its functional states, the IG shuttles between the EFL and the pore domain shedding new light onto how these regions tune channel function.

Binding characteristics of calpastatin domain L to NaV1.5 sodium channel and its IQ motif mutants

NaV1.5 channel is an integral membrane protein involved in the initiation and conduction of action potentials. IQ motif is located in the C-terminal domain of NaV1.5 sodium channel, which is highly conserved in human sodium channel subtypes. IQ motif is involved in the Ca2+-dependent regulation through interaction with the regulatory proteins such as calpastatin domain L (CSL). Mutations in SCN5A, the gene encoding NaV1.5 channel, have been linked to many cardiac arrhythmias, such as Long QT syndrome type 3 (LQT3) and Brugada syndrome (BRS). LQT3-associated mutations in NaV1.5 IQ motif, IQQ1909R and IQR1913H, have been reported to affect the late INa. A BRS-associated mutation in NaV1.5 IQ motif, IQA1924T, has been reported to affect the peak INa. But the detailed pathogenic mechanisms of LQT3 and BRS remains unclear. To explore the binding properties of CSL to IQ motif and its muants associated with LQT3/BRS, molecular docking and GST pull down assay were performed in this study. As a result, S58 and E59 in CSL activating channel effect region L54-64 were involved in the conformation of the CSL/IQWT complex by protein-protein docking. IQ motif could bind to CSL in a [CSL]-dependent and [Ca2+]-dependent manner by pull down assay. However, the binding affinities of IQQ1909R and IQR1913H to CSL were decreased and its reaction rates with CSL were slower. The binding characteristics of IQA1924T to CSL was opposite in a [Ca2+]-dependent manner and its binding efficacy became smaller. The changes of the binding characteristics of IQmutants to CSL would affect the regulation of NaV1.5 channel, which may be related to LQT3 and BRS.

Effects of Mexiletine on a Race-specific Mutation in Nav1.5 Associated With Long QT Syndrome.

The voltage-gated sodium channel Nav1.5 plays an essential role in the generation and propagation of action potential in cardiomyocytes. Mutations in Nav1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Nav1.5 mutations vary across race-ethnic groups. Here we investigated an Asian-specific mutation Nav1.5-P1090L associated with LQT syndrome. We found that Nav1.5-P1090L mutation perturbed the sodium channel function. It altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by P1090L. Mexiletine also modified the recovery from steady-state inactivation and the development of inactivation of P1090L. It rescued the dysfunctional inactivation of P1090L and reduced the P1090L channel’s availability.

The Human SCN9A R185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice.

The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in patients with small fiber neuropathy (SFN) having chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9aR185H mutant mouse model using the CRISPR/Cas9 technology. The Scn9aR185H mutant mice show no cellular alteration in the dorsal root ganglia (DRG) containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than the wild-type mice in the tail flick and hot plate tests, acetone, and von Frey tests for sensitivity to heat, cold, and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline, Gdaphen is based on general linear model (GLM) and random forest (RF) classifiers as well as a multifactor analysis of mixed data and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate, and von Frey tests, sex and genotype were found to be contributing most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the conditioned place preference (CPP) assay. Altogether, our results indicate that Scn9aR185H mice show a pain phenotype, suggesting that the SCN9AR185H mutation identified in patients with SFN having chronic pain contributes to their symptoms. Therefore, we provide genetic evidence for the fact that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by patients with SFN who have this mutation. These findings should aid in exploring further pain treatments based on the Nav1.7 channel.

Histamine Sensitization of the Voltage-Gated Sodium Channel Nav1.7 Contributes to Histaminergic Itch in Mice.

Itch, a common clinical symptom of many skin diseases, severely impairs the life quality of patients. Nav1.7, a subtype of voltage-gated sodium channels mainly expressed in primary sensory neurons, is responsible for the amplification of threshold currents that trigger action potential (AP) generation. Gain-of-function mutation of Nav1.7 leads to paroxysmal itch, while pharmacological inhibition of Nav1.7 alleviates histamine-dependent itch. However, the crosstalk between histamine and Nav1.7 that leads to itch is unclear. In the present study, we demonstrated that in the dorsal root ganglion (DRG) neurons from histamine-dependent itch model mice induced by compound 48/80, tetrodotoxin-sensitive (TTX-S) but not TTX-resistant Na+ currents were activated at more hyperpolarized membrane potentials compared to those on DRG neurons from vehicle-treated mice. Meanwhile, bath application of histamine shifted the activation voltages of TTX-S Na+ currents to the hyperpolarized direction, increased the AP frequency, and reduced the current threshold required to elicit APs. Further mechanistic studies demonstrated that selective activation of H1 but not H2 and H4 receptors mimicked histamine effect on TTX-S Na+ channels in DRG neurons. The protein kinase C (PKC) inhibitor GO 8963, but not the PKA inhibitor H89, normalized histamine-sensitized TTX-S Na+ channels. We also demonstrated that histamine shifted the activation voltages of Na+ currents to the hyperpolarized direction in Chinese hamster ovary (CHO) cells expressing Nav1.7. Importantly, selective inhibition of Nav1.7 by PF-05089771 significantly relieved the scratching frequency in a histamine-dependent itch model induced by compound 48/80. Taken together, these data suggest that activation of H1 receptors by histamine sensitizes Nav1.7 channels through the PKC pathway in DRG neurons that contributes to histamine-dependent itch.

Truncations of Nav1.5 carboxy-terminal domain differentially perturb channel function

The voltage-gated sodium channel (NaV1.5) is critical for cardiac function. Rapid activation of NaV1.5 supports the initiation of the action potential, while ensuing inactivation is essential for proper repolarization. Human channelopathic mutations in NaV1.5 have been linked to various cardiac maladies, including cardiac arrhythmia, atrial fibrillation, and dilated cardiomyopathies. The carboxy-terminal domain (CTD) of NaV1.5 is critical for fine-tuning channel inactivation and is well-recognized as a hotspot for channelopathic mutations.

IPSCs and DRGs: stepping stones to new pain therapies.

There is a pressing need for more effective nonaddictive treatment options for pain. Pain signals are transmitted from the periphery into the spinal cord via dorsal root ganglion (DRG) neurons, whose excitability is driven by voltage-gated sodium (NaV) channels. Three NaV channels (NaV1.7, NaV1.8, and NaV1.9), preferentially expressed in DRG neurons, play important roles in pain signaling in humans. Blockade of these channels may provide a novel approach to the treatment of pain, but clinical translation of preclinical results has been challenging, in part due to differences between rodent and human DRG neurons. Human DRG neurons and iPSC-derived sensory neurons (iPSC-SNs) provide new preclinical platforms that may facilitate the development of novel pain therapeutics.

Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.

Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.

Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels.

Spreading depolarizations (SDs) are involved in migraine, epilepsy, stroke, traumatic brain injury, and subarachnoid hemorrhage. However, the cellular origin and specific differential mechanisms are not clear. Increased glutamatergic activity is thought to be the key factor for generating cortical spreading depression (CSD), a pathological mechanism of migraine. Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of NaV1.1 (SCN1A) cause familial hemiplegic migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking NaV1.1 gain of function to CSD generation in FHM3. Thus, we reveal the key role of hyperactivity of GABAergic interneurons in a mechanism of CSD initiation, which is relevant as a pathological mechanism of Nav1.1 FHM3 mutations, and possibly also for other types of migraine and diseases in which SDs are involved.

A Buthus martensii Karsch scorpion sting targets Nav1.7 in mice and mimics a phenotype of human chronic pain.

Gain-of-function and loss-of-function mutations in Nav1.7 cause chronic pain and pain insensitivity, respectively. The preferential expression of Nav1.7 in the peripheral nervous system and its role in human pain signaling make Nav1.7 a promising target for next-generation pain therapeutics. However, pharmacological agents have not fully recapitulated these pain phenotypes, and because of the lack of subtype-selective molecular modulators, the role of Nav1.7 in the perception of pain remains poorly understood. Scorpion venom is an excellent source of bioactive peptides that modulate various ion channels, including voltage-gated sodium (Nav) channels. Here, we demonstrate that Buthus martensii Karsch scorpion venom (BV) elicits pain responses in mice through direct enhancement of Nav1.7 activity and have identified Makatoxin-3, an α-like toxin, as a critical component for BV-mediated effects on Nav1.7. Blocking other Nav subtypes did not eliminate BV-evoked pain responses, supporting the pivotal role of Nav1.7 in BV-induced pain. Makatoxin-3 acts on the S3-S4 loop of voltage sensor domain IV (VSD4) of Nav1.7, which causes a hyperpolarizing shift in the steady-state fast inactivation and impairs inactivation kinetics. We also determined the key residues and structure-function relationships for the toxin-channel interactions, which are distinct from those of other well-studied α toxins. This study not only reveals a new mechanism underlying BV-evoked pain but also enriches our knowledge of key structural elements of scorpion toxins that are pivotal for toxin-Nav1.7 interactions, which facilitates the design of novel Nav1.7 selective modulators.

Genetic and epigenetic of pain perception

Pain is the common reason why patient seeking for medical help. Recent studies, shows that there are various type of genes that have a role in pain perception. Genetic’s role include pain sensation Genome Wide Association Study, Single Nucleotide Polymorphism, and epigenetic in pain modulation. Recent studies shows that epigenetic mechanism can alter the expression of pronSetyaociceptive or antinociceptive gene that useful in managing pain from now on. In genes there are one or more polymorphisms that effect the expression of the protein products that later affect the pain response. Ion Channel is a protein membrrane that transporting ion in and out of a cell. This ion channel can change depends on the genes that made the protein. Recent studies shown that there’s more than 450 ion channel genes. From all of those ion channels, voltage gated sodium channel (Nav) tend to be investigated more deeply because Nav is the most common and widely distributed in human cell. Changes on those channels can cause neuropathic pain. Small Fibre Neuropathy caused by defect of fiber myelinated A-delta and unmyelinated C. Substitution of a single aminoalkanoic acid in gene SCN9A, a gene that encoding for Na+ channel Nav1.7, can cause changes in channel Nav1.7. Study shows that Small Fibre Neuropathy lesion in gene SCN9A has decreased after surgical pain sensitivity in cohort patients. There’s two types of inherited traits of pain sensation which is Mendellian and Non-Mendellian. Mendellian Inherited Traits show a relation between gene and a specific pain sensation that in recent studies show mutation in Nav1.7 ion channel. However, the Non Mendellian Inherited Traits said that Catechol O Methyltrasnferase, Guanosin Trifosfat, Cyclo Hydrolase and Nav1.9 have a very important role in pain sensation. This gene mutation information can help the clinician to give a better treatment strategies for patients.

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability.

Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.