Potassium channel blocking

Dauplais, M., Lecoq, A., Song, J., Cotton, J., Jamin, N., Gilquin, B., Roumestand, C., Vita, C., de Medeiros, C.L.C., Rowan, E.G., Harvey, A.L. and Menez, A. (1997) On the convergent evolution of animal toxins. Conservation of a diad of functional residues in potassium channel-blocking toxins with unrelated structures. Journal of Biological Chemistry 272, 4302 309. 

It is an alkaloid obtained from the bark of cinchona and is a dextro isomer of anti-malarial drug quinine. Its sodium channel blocking property results in an increased threshold for excitability and decreased automaticity. As a consequence of its potassium channel blocking properties, it prolongs action potential in most cardiac cells. 

Scorpion toxins are polypeptides containing 30-78 amino acids. They have their actions on sodium channels as well as at other locations. Charybodotoxin, from the scorpion Sun es quinquestriatus is a 37 amino acid peptide which has potassium channel blocking activity. The really toxic scorpions are found mainly in Mexico and North Africa. Fatalities usually... 

Colatsky TJ, Follmer CH, Starmer CF (1990) Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. Circulation 82 2235-2242... 

III Potassium channel blocking Amiodarone Bretylium Resistant ventricular fibrillation... 

Type I antiarrhythmics appear to share a single receptor site in the sodium channel. It should be noted, however, that a number of type I drugs have other electrophysiologic properties. For instance, quinidine has potent potassium channel blocking activity (manifest predominantly at low concentrations), as does A-acetylprocainamide (manifest predominantly at high concentrations), the primary metabolite of procainamide. Additionally, propafenone has /3-blocking actions. 

We have designed and synthesized a series of T-shaped reversible potassium channel pore blockers. These small molecules are proposed to occlude the potassium channel pore by the insertion of an ammonium terminated ligand. This mechanism of action is well precedented in the potassium channel blocking mechanism of the natural toxin peptides isolated from snakes, spiders, and scorpions. Further evidence of the binding hypothesis will be discussed. 

Lopatin AN, Makhina EN, Nichols CG (1994) Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature (Lond) 372 366-369 Lopatin AN, Makhina EN, Nichols CG (1995) The mechanism of inward rectification of potassium channels long-pore plugging by cytoplasmic polyamines. J Gen Physiol 106 923-955 Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE (2002) Alterations in conserved Kir channel-PlP2 interactions underlie channelopathies. Neuron 34 933-944 Lu Z (2004) Mechanism of rectification in inward-rectifier K+ channels. Annu Rev Physiol 66 103-129... 

Savarin, P., Guenneugues, M., Gilquin, B., Lamthanh, H., Gasparini, S., Zinn-Justin, S., and Menez, A. (1998) Three-dimensional structure of K-conotoxin PVIIA, a novel potassium channel-blocking toxin from cone snails. Biochemistry, 37, 5407-5416. 

Anderson, A. J., and Harvey, A. L. (1988). Effects of the potassium channel blocking dendrotoxins on acetylcholine release and motor nerve terminal activity. Br. J. Pharmacol. 93 215-221. 

Rowan, E.G. and Harvey, A.L. (1988) Potassium channel blocking actions of P-bungarotoxin and related toxins on mouse and frog motor nerve terminals. Br. J. Pharmacol. 94, 839-847. 

---