How do sodium channels work

After eating, the first is sensory nerve paralysis, followed by motor nerve paralysis, which eventually leads to limb weakness or even inability to exercise. This is mainly because both are sodium channel inhibitors, which can specifically bind to the neurotoxin binding site 1 on the sodium channel located on the ring formed between S5 and S6 in DI-DIV , thereby inhibiting nerve conduction, eventually leading to limb paralysis. Clinical studies have shown that the analgesic effect of TTX is times than thatof morphine; the local anesthetic effect is times than that of procaine hydrochloride.

As early as , Southcott has demonstrated that STX can inhibit nerve conduction for a long time, and its local anesthetic effect is , times as that of procaine. In , when Berde et al. Therefore, a single injection of drugs can relieve pain for a long time, and ultimately reduce the need for addictive drugs such as opioids after surgery.

In , Sahadev et al. The results showed that the thermal pain block duration of the rats continued to be 6. Therefore, when TTX or STX is combined with other anesthetic analgesic drugs morphine, cocaine, bupivacaine, dexamethasone, etc. Certain local anesthetics and analgesics circulating on the market are amines containing aromatic groups like tetrodotoxin and saxitoxin.

It can suppress or reduce pain at very low concentrations and has a good effect on the treatment of neuropathic pain. When a spider preys or defies an enemy, its venom gland can paralyze or even kill prey or natural enemies by secreting spider toxins. This is mainly since spider toxins contain a variety of molecularly-sized, disulfide-rich peptide neurotoxins that affect the normal activities of ion channels in neurons, including sodium channels, potassium channels, and calcium channels.

These neurotoxins play an important role in medical research, and some of them are clinically used to relieve pain or treat diseases such as arrhythmia.

According to the literature, nearly one-third of the total number of spider toxins is targeted at sodium channels. It is conservatively estimated that spider venom contains at least 10 million biologically active peptides. However, the peptides with ion channel regulation function reported in the literature are only about 0. Therefore, there are many new spider toxins in spider venom that need to be discovered, characterized and studied, which will greatly promote the development and utilization of analgesic and local anesthetic drugs in the future.

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Contact us. Privacy and Cookie Policy. Sponsors list. Voltage-gated sodium channels Na V : Introduction. Introduction Voltage-gated sodium channels are responsible for action potential initiation and propagation in excitable cells, including nerve, muscle, and neuroendocrine cell types [ 30 , 32 ]. Figure 1. The primary structures of the subunits of the voltage-gated sodium channels. Bold lines represent the polypeptide chains of each subunit, with length approximately proportional to the number of amino acid residues in the brain sodium channel subtypes.

Click image for full size. Sodium channel interacting proteins Many proteins have been shown to interact with sodium channels transiently in the context of channel regulation, including several protein kinases and G proteins [ 7 ].

Sodium channel structure at atomic resolution Sodium channel architecture has been revealed in three-dimensions by determination of the crystal structure of bacterial sodium channels at high resolution 2. Figure 2. Structure of the bacterial sodium channel NavAb. The four pore modules in the center are rigid in the crystal structure and therefore are blue. The four voltage-sensing modules surround the pore and are more mobile, as illustrated by warmer colors. Architecture of the NavAb pore.

Glu side-chains, purple; pore volume, grey. The P and P2 alpha helices that form the scaffold for the selectivity filter and outer vestibule are shown in green and red, respectively. Side view of NavAb. The structural components of one subunit are highlighted , transmembrane segments S1-S6. Side view of the selectivity filter. Glu purple interactions with Gln, Ser and the backbone of Ser are shown in the far subunit; putative cations or water molecules red spheres, Ion EX.

Electron-density around Leu grey and a bound water molecule are shown in gray. The structure of the voltage sensor. From Hodgkin-Huxley model, the total cell membrane current, I, can be calculated by Eq.

In , an extracellular recording technique, electrocardiography, was invented by Willem Einthoven Nobel Laureate ; in , intracellular recording technique was developed by Alan Hodgkin and Andrew Huxley Nobel Laureates ; and in , Erwin Neher and Bert Sackmann Noble Laureates succeeded in measuring the ionic current of single channels in the cell membrane by developing patch clamp technique.

These works were fundamental in revealing the physiological function of ion channels. Since then, the field of electrophysiology had undergone rapid evolution, especially after the introduction of automated patch clamp in the early s.

Manual patch clamp technique employs glass microelectrode s with desired filling solution and tip diameter to perform either voltage or current clamp. By applying different following-up manipulations, the patch-clamp can be achieved in four configurations: cell-attached patch, whole-cell patch, inside-out patch, and outside-out patch, as shown in Figure 3. Manual patch clamp configurations and procedures.

After a cell is approached by a pipette A , a high-resistance seal is achieved through application of negative pressure, resulting in the cell-attached configuration B. Further application of negative pressure ruptures the membrane, resulting in the whole-cell configuration, i. Inside-out and outside-out configurations are achieved by pulling the pipette away from the cell D and E. F An equivalent electrical circuit of a cell in whole-cell configuration during acquisition of data.

Modified from [ 5 ]. Many other electrophysiological techniques have been developed for various applications, including extracellular recordings such as electroencephalography EEG , electrocardiography ECG or EKG , and electromyography EMG for clinical diagnosis; artificial lipid bilayer recording for studying activities of reconstituted ion channel proteins; automated patch clamp recording to enable high-throughput recordings; and optogenetics to employ light to switch on and off ion channel activities.

The technology evolution has brought the ion channel research and drug discovery to a new era, which will be discussed in later part of this chapter. Nav channels were the first ion channel family discovered back in [ 1 , 4 ] and cloned in [ 6 ]. Its pedigree spans across prokaryotic and eukaryotic kingdoms [ 7 ].

The BacNavs regulate the survival response to extreme pH, electrophiles, and hypoosmotic shock. Despite their markedly difference in physiology function, voltage dependence and kinetics, BacNavs share common features of mammalian Nav channels, thus serving as surrogates in the study of molecular evolution and channel architecture. Nav family belongs to the voltage-gated ion channel VGIC superfamily, with less intrafamily variation comparing to the other two VGIC families, voltage-gated potassium channels Kvs and voltage-gated calcium channels Cavs.

The first four transmembrane segments form a voltage-sensing domain VSD and the last two form the pore domain PD. The central PD is responsible for ion-transduction through the structural top funnel, selectivity filter and gate, and all other domains are served as regulatory modlues for activation, fast and slow inactivation, albeit with different natures and structures. A typical Nav channel has at least three distinct states, resting closed , activated open , inactivated closed , which itself includes fast-inactivated within milliseconds and slow-inactivated seconds , and recovering from inactivation repriming , which is a period in which the channel is not available to open in response to a depolarization.

Each Nav channel can be characterized by these different voltage-dependent biophysiological preporties, and pharmacological perporties according to its expression pattern and modulation. Structures of voltage-gated sodium channels. Modified from [ 12 , 15 ]. A Schematic representation of BacNav. B Schematic representation of eukaryotic Navs. E The pore domain sodium permeation path including selectivity filter, central cavity, and intracellular activation gate are colored in brown and annotated with pore radius.

In human, there are 9 Nav channels Nav1. Thus, Nax was classified as a different Nav subfamily type 2 [ 16 , 17 ]. Due to their fundamental role in regulating central and peripheral nervous systems function, skeletal muscle contraction and heart rhythm, much of the early works on Navs involved characterizing their expression patterns, biophysiological properties, structure-function, and molecular pharmacology.

Compared to Cav and Kv channel family, the rise of Nav family is relatively recent [ 18 ]. This is supported by the finding that the four domains of Navs have higher similarity to their corresponding domains in the Cav channels than to each other. The ancestral Navs and Cavs genes might have evolved by two rounds of gene duplication, i. In choanoflagellate the sister group of animals , the rapid long-distance communication among excitable cells is achieved at the emergence of Metazoa represented by bilaterian animals and cnidarians through the use of Nav channel [ 20 , 21 ].

The gene organization, biophysical, and pharmacological properties of invertebrate sodium channels are largely similar to their mammalian counterparts, suggesting that the primordial Nav channels were established before the evolutionary separation of the invertebrates from the vertebrates, and evolution of Navs played a critical role in the emergence of nervous systems in animals [ 19 , 22 ]. Of note, sodium selectivity might be acquired independently in BacNav and mammalian Nav channels as indicated by phylogenetic analysis [ 23 ].

Therefore, BacNav channels can serve as models for studying Navs structure function, but evolutionary variation should be taken into consideration. Historically, the tissue distribution of mammalian Nav isoforms was obtained by methods such as quantitative PCR, expressed sequence tag EST profiling, and pharmacology study using isoform selective toxins.

Now, we know that Nav1. Interestingly, all of these CNS-enriched isoforms are sensitive to tetrodotoxin TTX at nanomolar concentrations, and their genes are clustered on chromosome 2 in both mice and humans. Sodium channel body atlas in human. More sensitive approaches have detected Nav1. These two Nav isoforms can be distinguished from each other and from the CNS isoforms on the basis of toxin sensitivity.

Adult skeletal muscle-enriched Nav1. In addition, Nav1. This PNS-specific localization of Nav1. The structure complexity and high-sequence homology make it difficult to design subtype-selective drugs.

In , the first X-ray crystal structure of bacterial Arcobacter butzleri Nav channels NavAb was determined [ 32 ]. Subsequently, structures for several BacNavs and a BacNav-human Nav chimeric channel have been resolved, representing closed [ 33 , 34 ], open [ 34 , 35 ], and potentially inactive states of the channels [ 36 , 37 ].

In , the first two eukaryotic Nav structures for American cockroach and electric eel Ee Nav1. Findings from crystal and cryo-EM structures are mostly consistent, and collectively provided important insights into Nav channel structure-function and structure-based drug design. Voltage-sensing domains VSDs. The S1 to S4 segments form voltage-sensing domain. There are four VSDs in a sodium channel.

These charge clusters move toward the extracellular surface upon membrane depolarization and return to their resting positions upon membrane repolarization. Thus, the outward and inward movements of S4 result in channel opening and closing, respectively.

For examples, the four VSDs have nonconserved intra- and extracellular loops, and the different charge clusters in S4, i. Also, the S2 in each VSD also makes asymmetric functional contributions to Nav channel activation and inactivation [ 38 ]. The functional entities along the ion permeation pathway in PD include the selectivity filter SF , the central cavity, and the intracellular activation gate, as shown in Figure 4E.

The outer vestibule and selectivity filter are formed in P-loop reentering membrane segments, designated as P1-SF-P2 funnel. The outer vestibule and SF structures were further discerned by using bacteria KcsA channel X-ray structure as template and guanidinium toxins TTX and saxitoxin, STX , which successfully defined the first pharmacological relevant site on Nav channels, site 1 [ 42 ]. After that, local anesthetic binding site was determined within the four fenestrations in PD, each with distinct shape and size [ 13 , 43 ].

Activation gate: the activation gate of Nav channels was originally predicted to be at the inner end of the pore based on the study of local anesthetics, which exhibit usage-dependent blockage [ 46 , 47 ]. Recent cryo-EM structures confirmed that this activation gate is located at the cytoplasmic boundary level of the membrane [ 12 ].