scholarly journals Bacterial Voltage-Gated Sodium Channels (BacNaVs) from the Soil, Sea, and Salt Lakes Enlighten Molecular Mechanisms of Electrical Signaling and Pharmacology in the Brain and Heart

2015 ◽  
Vol 427 (1) ◽  
pp. 3-30 ◽  
Author(s):  
Jian Payandeh ◽  
Daniel L. Minor
Keyword(s):  
Sodium Channels ◽  
Molecular Mechanisms ◽  
Salt Lakes ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Electrical Signaling ◽  
The Brain

Molecular mechanisms of neurotoxin action on voltage-gated sodium channels

Biochimie ◽  
2000 ◽  
Vol 82 (9-10) ◽  
pp. 883-892 ◽  
Author(s):  
S Cestèle
Keyword(s):  
Sodium Channels ◽  
Molecular Mechanisms ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Interpreting the functional role of a novel interaction motif in prokaryotic sodium channels

2017 ◽  
Vol 149 (6) ◽  
pp. 613-622 ◽  
Author(s):  
Altin Sula ◽  
B.A. Wallace
Keyword(s):  
Sodium Channels ◽  
Functional Role ◽  
Structural Features ◽  
Channel Activation ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Channel Opening ◽  
Activated State ◽  
Electrical Signaling

Voltage-gated sodium channels enable the translocation of sodium ions across cell membranes and play crucial roles in electrical signaling by initiating the action potential. In humans, mutations in sodium channels give rise to several neurological and cardiovascular diseases, and hence they are targets for pharmaceutical drug developments. Prokaryotic sodium channel crystal structures have provided detailed views of sodium channels, which by homology have suggested potentially important functionally related structural features in human sodium channels. A new crystal structure of a full-length prokaryotic channel, NavMs, in a conformation we proposed to represent the open, activated state, has revealed a novel interaction motif associated with channel opening. This motif is associated with disease when mutated in human sodium channels and plays an important and dynamic role in our new model for channel activation.

scholarly journals Distribution of TTX-sensitive voltage-gated sodium channels in primary sensory endings of mammalian muscle spindles

2017 ◽  
Vol 117 (4) ◽  
pp. 1690-1701 ◽  
Author(s):  
Dario I. Carrasco ◽  
Jacob A. Vincent ◽  
Timothy C. Cope
Keyword(s):  
Sodium Channels ◽  
Molecular Mechanisms ◽  
Mammalian Species ◽  
Muscle Spindles ◽  
Tonic Firing ◽  
Muscle Stretch ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Nav Channels ◽  
Sensory Endings

Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV1.6 isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV1.6 immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV1.6 IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV1.6 IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV1.1, predominantly in sensory terminals together with NaV1.6 and for NaV1.7, mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles. NEW & NOTEWORTHY The molecular mechanisms underlying mechanosensory signaling responsible for proprioceptive functions are not completely elucidated. This study provides the first evidence that voltage-gated sodium channels (NaVs) are expressed in the spindle primary sensory ending, where NaVs are found at every site involved in transduction or encoding of muscle stretch. We propose that NaVs contribute to multiple steps in sensory signaling by muscle spindles as it does in other types of slowly adapting sensory neurons.

scholarly journals Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

2021 ◽  
Vol 12 ◽  
Author(s):  
Ibitayo Abigail Ademuwagun ◽  
Solomon Oladapo Rotimi ◽  
Steffen Syrbe ◽  
Yvonne Ukamaka Ajamma ◽  
Ezekiel Adebiyi
Keyword(s):  
Ion Channel ◽  
Sodium Channel ◽  
Sodium Channels ◽  
De Novo ◽  
Single Gene ◽  
Voltage Gated ◽  
Functional Studies ◽  
Voltage Gated Sodium Channels ◽  
Genomic Studies ◽  
The Brain

Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are SCN1A, SCN1B, SCN2A, SCN3A, and SCN8A genes that are highly expressed in the brain. Genomic studies have revealed inherited and de novo mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

scholarly journals A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels

2017 ◽  
Author(s):  
Mohammad-Reza Ghovanloo ◽  
Mena Abdelsayed ◽  
Colin H. Peters ◽  
Peter C. Ruben
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channels ◽  
Muscular Contraction ◽  
Periodic Paralysis ◽  
Ph Sensitivity ◽  
Voltage Gated ◽  
Blood Ph ◽  
Voltage Gated Sodium Channels ◽  
Missense Mutant ◽  
Electrical Signaling

ABSTRACTSkeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include both myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the ‘‘skeletal muscle’’ voltage-gated sodium channel, Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results indicate that, unlike in WT Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we also predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger myotonia or periodic paralysis in P1158S patients.SIGNIFICANCE STATEMENTVoltage-gated sodium channels (Nav) contribute to the physiology and pathophysiology of electrical signaling in excitable cells. Nav subtypes are expressed in a tissue-specific manner, thus they respond differently to physiological modulators. For instance, the cardiac subtype, Nav1.5, can be modified by changes in blood pH; however, the skeletal muscle subtype, Nav1.4, is mostly pH-insensitive. Nav1.4 mutants can mostly cause either hyper-or hypo-excitability in skeletal muscles, leading to conditions such as myotonia or periodic paralysis. P1158S uniquely causes both phenotypes. This study investigates pH-sensitivity in P1158S, and describes how physiological pH changes can push P1158S to cause myotonia and periodic paralysis.

scholarly journals Insights into the origins of fish hunting in venomous cone snails from studies of Conus tessulatus

2015 ◽  
Vol 112 (16) ◽  
pp. 5087-5092 ◽  
Author(s):  
Joseph W. Aman ◽  
Julita S. Imperial ◽  
Beatrix Ueberheide ◽  
Min-Min Zhang ◽  
Manuel Aguilar ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Molecular Mechanisms ◽  
Prey Capture ◽  
Sequence Similarity ◽  
Cone Snail ◽  
Evolutionary Transitions ◽  
Voltage Gated ◽  
Channel Inactivation ◽  
Voltage Gated Sodium Channels ◽  
Cone Snails

Prey shifts in carnivorous predators are events that can initiate the accelerated generation of new biodiversity. However, it is seldom possible to reconstruct how the change in prey preference occurred. Here we describe an evolutionary “smoking gun” that illuminates the transition from worm hunting to fish hunting among marine cone snails, resulting in the adaptive radiation of fish-hunting lineages comprising ∼100 piscivorous Conus species. This smoking gun is δ-conotoxin TsVIA, a peptide from the venom of Conus tessulatus that delays inactivation of vertebrate voltage-gated sodium channels. C. tessulatus is a species in a worm-hunting clade, which is phylogenetically closely related to the fish-hunting cone snail specialists. The discovery of a δ-conotoxin that potently acts on vertebrate sodium channels in the venom of a worm-hunting cone snail suggests that a closely related ancestral toxin enabled the transition from worm hunting to fish hunting, as δ-conotoxins are highly conserved among fish hunters and critical to their mechanism of prey capture; this peptide, δ-conotoxin TsVIA, has striking sequence similarity to these δ-conotoxins from piscivorous cone snail venoms. Calcium-imaging studies on dissociated dorsal root ganglion (DRG) neurons revealed the peptide’s putative molecular target (voltage-gated sodium channels) and mechanism of action (inhibition of channel inactivation). The results were confirmed by electrophysiology. This work demonstrates how elucidating the specific interactions between toxins and receptors from phylogenetically well-defined lineages can uncover molecular mechanisms that underlie significant evolutionary transitions.

scholarly journals Nanometer-Scale Imaging of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels

2021 ◽  
Author(s):  
Hui Liu ◽  
Hong-Gang Wang ◽  
Geoffrey S Pitt ◽  
Zhe Liu
Keyword(s):  
Membrane Proteins ◽  
Sodium Channels ◽  
Cellular Localization ◽  
Protein Localization ◽  
Developmental Regulation ◽  
Cell Communication ◽  
Membrane Excitability ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
The Brain

Membrane excitability and cell-to-cell communication in the brain are tightly regulated by diverse ion channels and receptor proteins localized to distinct membrane compartments. Currently, a major technical barrier in cellular neuroscience is lack of reliable methods to label these membrane proteins and image their sub-cellular localization and dynamics. To overcome this challenge, we devised optical imaging strategies that enable systematic characterization of subcellular composition, relative abundances and trafficking dynamics of membrane proteins at nanometer scales in cultured neurons as well as in the brain. Using these methods, we revealed exquisite developmental regulation of subcellular distributions of voltage-gated sodium channel (VGSC) Nav1.2 and Nav1.6, settling a decade long debate regarding the molecular identity of sodium channels in dendrites. In addition, we discovered a previously uncharacterized trafficking pathway that targets Nav1.2 to unmyelinated fragments in the distal axon. Myelination counteracts this pathway, facilitating the installment of Nav1.6 as the dominant VGSC in the axon. Together, these imaging approaches unveiled compartment-specific trafficking mechanisms underpinning differential membrane distributions of VGSCs and open avenues to decipher how membrane protein localization and dynamics contribute to neural computation in the brain.

Contribution of tetrodotoxin-sensitive voltage-gated sodium channels (NaV1) to action potential discharge from mouse esophageal tension mechanoreceptors

2021 ◽  
Author(s):  
Stephen Hadley ◽  
Mayur J Patil ◽  
Nikoleta Pavelkova ◽  
Marian Kollarik ◽  
Thomas E Taylor-Clark
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Esophageal Motility ◽  
Critical Role ◽  
Inhibitory Effect ◽  
Sensory Afferents ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Almost All ◽  
Electrical Signaling

Action potentials depend on voltage-gated sodium channels (NaV1s), which have nine alpha subtypes. NaV1 inhibition is a target for pathologies involving excitable cells such as pain. However, because NaV1 subtypes are widely expressed, inhibitors may inhibit regulatory sensory systems. Here, we investigated specific NaV1s and their inhibition in mouse esophageal mechanoreceptors - non-nociceptive vagal sensory afferents that are stimulated by low threshold mechanical distension, which regulate esophageal motility. Using single fiber electrophysiology, we found mechanoreceptor responses to esophageal distension were abolished by tetrodotoxin. Single cell RT-PCR revealed that esophageal-labeled TRPV1-negative vagal neurons expressed multiple tetrodotoxin-sensitive NaV1s: NaV1.7 (almost all neurons) and NaV1.1, NaV1.2 and NaV1.6 (in ~50% of neurons). Inhibition of NaV1.7, using PF-05089771, had a small inhibitory effect on mechanoreceptor responses to distension. Inhibition of NaV1.1 and NaV1.6, using ICA-121341, had a similar small inhibitory effect. The combination of PF-05089771 and ICA-121341 inhibited but did not eliminate mechanoreceptor responses. Inhibition of NaV1.2, NaV1.6 and NaV1.7 using LSN-3049227 inhibited but did not eliminate mechanoreceptor responses. Thus all four tetrodotoxin-sensitive NaV1s contribute to action potential initiation from esophageal mechanoreceptors terminals. This is different to those NaV1s necessary for vagal action potential conduction, as demonstrated using GCaMP6s imaging of esophageal vagal neurons during electrical stimulation. Tetrodotoxin-sensitive conduction was abolished in many esophageal neurons by PF-05089771 alone, indicating a critical role of NaV1.7. In summary, multiple NaV1 subtypes contribute to electrical signaling in esophageal mechanoreceptors. Thus inhibition of individual NaV1s would likely have minimal effect on afferent regulation of esophageal motility.

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