Biophysics of voltage-dependent ion channels

Lecture 4
Pharmacology of voltage-gated sodium channels. Sodium channel channelopaties

Phylogeny of voltage-activated channels

Anderson PAV, Greenberg RM: Phylogeny of ion channels: clues to structure and function. Comp Biochem Physiol B Biochem Mol Biol 2001, 129:17-28.

General structure of voltage-activated channel

Structure of voltage-activated sodium channel

4 9
A.L. George, J Clin Invest. 2005 Aug;115(8):1990-9.

Molecular diversity of voltage-activated sodium channel

skeletal cardiac

Neuron, Vol. 28, 365368, November, 2000

Molecular diversity of human sodium channel

A.L. George, J Clin Invest. 2005 Aug;115(8):1990-9.

Sodium channels have fast kinetics of activation and inactivation

Chen et al., European Journal of Neuroscience, Vol. 12, pp. 42814289, 2000

Structural bases of sodium channel inactivation

Yu and Catterall Genome Biology 2003 4:207

All sodium channels have similarly fast kinetics of activation and inactivation

neuronal

skeletal

cardiac
Yu et al., J Neurosci. 2003 Aug 20;23(20):7577-85.

Sodium channels generate repetitive firing

Swensen and Bean, The Journal of Neuroscience, 2003, 23(29):96509663

Sodium channel starts the action potential

http://www.cvpharmacology.com/

Toxins modulating sodium channels

N. Ogata and Y. Ohishi, Jpn. J. Pharmacol. 88, 365 377 (2002)

Toxins modulating sodium channels - activators

veratridine

batrachotoxin
aconitine grayanotoxin b-scorpion toxin

Toxins modulating sodium channels - activators

b-scorpion toxin

Schiavon, E. et al. J. Biol. Chem. 2006;281:20326-20337

Toxins modulating sodium channels - activators

b-scorpion toxin

Schiavon, E. et al. J. Biol. Chem. 2006;281:20326-20337

Toxins modulating sodium channels - blockers

tetrodotoxin
saxitoxin local anesthetics (procaine, tetracaine, chloroprocaine,
lidocaine, mepivacaine, bupivacaine, etidocaine)

antiepileptic drugs (carbamezepine, phenytoin, fosphenytoin,

oxcarbazepine, lamotrigine, zonisammide)

antiarrhythmic drugs (amiodarone, quinidine, lidocaine,

flecainide)

Toxins modulating sodium channels - blockers

Tetrodotoxin
1 mM 30 nM

1 nM

Toxins modulating sodium channels - blockers

Golomb, D. et al. J Neurophysiol 96: 1912-1926 2006; doi:10.1152/jn.00205.2006

Antiarrhythmic sodium channel blockers

http://www.cvpharmacology.com/

Sodium channel related channelopathies

muscular disorders

generalized epilepsy ventricular fibrilation

long QT

N. Ogata and Y. Ohishi, Jpn. J. Pharmacol. 88, 365 377 (2002)

Sodium channel related channelopathies

Sodium channel related channelopathies

AL George J Clin Invest 115: 1990-1999, 2005

Sodium channel related channelopathies

AL George J Clin Invest 115: 1990-1999, 2005

Sodium channel related channelopathies

Enhanced ITO

AL George J Clin Invest 115: 1990-1999, 2005

Summary
sodium channels have fast kinetics 9 known mammalian channels have similar voltage dependent properties channelopathies include muscular, cardiac and neuronal disorders

Recommended reading:
W. A. Catterall, A. L. Goldin, S. G. Waxman, Pharmacol Rev 57:397 409, 2005 Alfred L. George, The Journal of Clinical Investigation 115: 1990-1999, 2005