Sodium Channels

Voltage-gated sodium channels are present in most excitable cell membranes and play an important role in generating action potentials. A variety of toxins and chemicals are known to either block or modulate sodium channels and have proven invaluable in investigating the physiological characteristics of these channels. Most notably, tetrodotoxin (TTX), isolated from puffer fish, is a potent and selective blocker of sodium channels. Saxitoxin (STX), a toxin isolated from dinoflagellates, was also found to have the same blocking action as TTX. The sodium channels present in brain, along with those found in peripheral nerves and skeletal muscle, are highly sensitive to TTX/STX at nanomolar concentrations, whereas some sodium channels in the heart are blocked at concentrations in the micromolar range, and TTX-resistant sodium channels in dorsal root ganglion neurons are only blocked at concentrations approaching 100 mM.

Structurally, the sodium channels of brain comprise one α subunit of 260 kDa, one β1 subunit of 36 kDa, and one β2 subunit of 33 kDa, forming a heterotrimeric structure. β3 may substitute for β1 and β4 for β2 in these brain sodium channel complexes. The sodium channels of skeletal muscle consist of one α and one β1-like subunit, whereas those of the heart and peripheral neurons are likely to be complexes of α, β and possibly other proteins/subunits, in unknown stoichiometry.

A variety of toxins and chemicals that modulate the function of sodium channels have been discovered and many of these are now being used as chemical tools to study these ion channels. These may be classified into several groups based on the mechanisms of modification of channel gating kinetics and on the binding sites. TTX, STX and µ-conotoxins bind to neurotoxin receptor site 1 to block sodium channels. Batrachotoxin, grayanotoxins, veratridine and aconitine alter the kinetics and voltage dependence of sodium channel activation and inhibit sodium channel inactivation through binding to neurotoxin receptor site 2. The combination of effects of these toxins causes persistent activation of sodium channels at the resting membrane potential. Sea anemone toxins and α-scorpion toxins block the sodium channel inactivation by binding to neurotoxin receptor site 3. The protease pronase and the chemical reagents N-bromo-acetamide and chloramine-T also block inactivation, but their exact sites of action are unknown. α-scorpion toxins shift the voltage dependence of activation negatively by binding to neurotoxin receptor site 4. Brevetoxins and ciguatoxins are similar to batrachotoxin and other site 1 toxins in their alteration of the kinetics and voltage dependence of activation and inhibition of inactivation, but brevetoxins and ciguatoxins bind to neurotoxin receptor site 5. The pyrethroid insecticides alter the voltage dependence and kinetics of both activation and inactivation of sodium channels and appear to bind to neurotoxin receptor site 6.

Sensory ganglion neurons (e.g. dorsal root and nodose ganglia), particularly those associated with small-diameter afferent fibers, express sodium channels that are highly resistant to TTX and play an important role in nociceptive mechanisms. Recent research efforts have focused on the development of agents selective for the TTX-resistant sodium channels of dorsal root ganglia, in anticipation that these might prove to be novel analgesic drugs.

Numerous clinically used drugs block sodium channels. Local anesthetics used in control of acute pain, antiarrhythmic drugs used in therapy of cardiac arrhythmias, and some antiepileptics used in control of seizures all bind to a common local anesthetic receptor site on sodium channels. Many of these drugs exhibit use-dependent block, a characteristic crucial for their therapeutic effects, as the channel block becomes more potent during rapid firing in arrhythmic or epileptic conditions.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Nomenclaturea NaV1.1 NaV1.2 NaV1.2a NaV1.3 NaV1.4
Previous Names I II IIA III μ1
Primary Source CNS CNS (neonatal) CNS (adult) CNS (embryonic) Skeletal muscle
Structural Information 2009 aa (rat) 2005 aa (rat) 2005 aa (rat) 1951 aa (rat) 1840 aa (rat)
Subunits α, β1-β4 α, β1-β4 α, β1-β4 α, β1-β4 α, β1
Conductance   20-25 pS 20-25 pS   20-25 pS
Ionic Selectivity Na+ > K+ > Ca2+ Na+ > K+ > Ca2+ Na+ > K+ > Ca2+ Na+ > K+ > Ca2+ Na+ > K+ > Ca2+
Blockers  
Neurotoxin Receptor Site 1  
TTX 10 nM 10 nM 10 nM 10 nM 10 nM
STX 2 nM 2 nM 2 nM 2 nM 2 nM
μ-Conotoxin N/A N/A N/A N/A Active
Local Anesthetic Receptor Site Local Anesthetics (L5647, P9879)b
Class I Antiarrhythmic Drugs
Phenytoin (D4505)
Carbamazepine (C4024)
Lamotrigine (L3791)
Modulators  
Neurotoxin Receptor Site 2 (Enhance activation and block inactivation) Batrachotoxin
Grayanotoxin
Veratridine (V5754)
Aconitine (A8001)
Neurotoxin Receptor Site 3 (Slow inactivation) α-Scorpion toxins
Sea anemone toxins (A7475)
Neurotoxin Receptor Site 4 (Enhance activation) β-Scorpion toxins
Neurotoxin Receptor Site 5 (Enhance activation and block inactivation) Brevetoxins
Ciguatoxin
Versutoxin
Neurotoxin Receptor Site 6 (Enhance activation and block inactivation) Pyrethoid insecticides
Radioligands [3H]-Brevetoxin
[3H]-Batrachotoxinin A 20 α-benzoate
[3H]-Saxitoxin
Primary Tissue Expression CNS CNS CNS CNS Skeletal muscle
Physiological Function Action potential initiation and conduction, synaptic integration Action potential initiation and conduction, synaptic integration Action potential initiation and conduction, synaptic integration Action potential initiation and conduction, synaptic integration Action potential initiation and conduction, synaptic integration
Disease Relevance Epilepsy, chronic pain Epilepsy Epilepsy Epilepsy, chronic pain Periodic paralysis, paralysis

 

 

Nomenclaturea NaV1.5 NaV1.6 NaV1.7 NaV1.8 NaV1.9
Previous Names h1 VI PN1 PN3/SNS SNS2
Primary Source Heart CNS Sympathetic and dorsal root ganglia Dorsal root ganglia Dorsal root ganglia
Structural Information 2019 aa (rat) 1976 aa (rat) 1984 aa (rat) 1957 aa (rat) 1765 aa (rat)
Subunits α, β1-β4 α, β α, β α, β α, β
Conductance 20-25 pS        
Ionic Selectivity Na+ > K+ > Ca2+ Na+ > K+ > Ca2+ Na+ > K+ > Ca2+ Na+ > K+ > Ca2+ Na+ > K+ > Ca2+
Blockers  
Neurotoxin Receptor Site 1  
TTX 1 μM 10 nM 10 nM ≥ 50 mM ≥ 50 mM
STX Active Active Active Not known Not known
μ-Conotoxin N/A N/A N/A N/A N/A
Local Anesthetic Receptor Site Local Anesthetics (L5647, P9879)b
Class I Antiarrhythmic Drugs
Phenytoin (D4505)
Carbamazepine (C4024)
Lamotrigine (L3791)
N/A N/A
Modulators  
Neurotoxin Receptor Site 2 (Enhance activation and block inactivation) Batrachotoxin
Grayanotoxin
Veratridine (V5754)
Aconitine (A8001)
N/A N/A
Neurotoxin Receptor Site 3
(Slow inactivation)
α-Scorpion toxins
Sea anemone toxins (A7475)
N/A N/A
Neurotoxin Receptor Site 4 (Enhance activation) β-Scorpion toxins N/A N/A
Neurotoxin Receptor Site 5 (Enhance activation and block inactivation) Brevetoxins
Ciguatoxin
Versutoxin
N/A N/A
Neurotoxin Receptor Site 6 (Enhance activation and block inactivation) Pyrethoid insecticides N/A N/A
Radioligands [3H]-Brevetoxin
[3H]-Batrachotoxinin A 20 α-benzoate
[3H]-Saxitoxin
N/A N/A
Primary Tissue
Expression
Heart CNS PNS DRG DRG
Physiological Function Action potential initiation and conduction Action potential initiation and conduction, synaptic integration
Action potential initiation and conduction
Action potential initiation and conduction Action potential initiation and conduction
Disease Relevance Arrhythmia Pain Chronic pain Chronic pain Chronic pain

 

Footnotes

a) This nomenclature, proposed by Goldin et al. in Neuron, 28, 365-368 (2000) has been reviewed and accepted by the Nomenclature Committee of IUPHAR.

b) Commonly used local anesthetics include Lidocaine (L5647), Mexiletine (M2727), Procainamide (P9391), Procaine (P9879), Flecainide (F6777) and Tetracaine (T7508). Typically, these local anesthetic, antiarrhythmic, and antiepileptic drugs have similar affinity for NaV1.1-1.7 and reduced affinity for NaV1.8 and NaV1.9.

 

Abbreviations

CNS: Central nervous system
DRG: Dorsal root ganglion
PNS: Peripheral nervous system
STX: Saxitoxin
TTX: Tetrodotoxin

 

Similar Products


     

References