Kaliotoxin

Kaliotoxin (KTX) is an ion channel toxin which inhibits potassium flux through the Kv1.3 voltage-gated potassium channel and calcium-activated potassium channels by physically blocking the channel-entrance and secondly KTX induces a conformational change in the K⁺-selectivity filter of the channel.

ource

KTX is a neurotoxin derived from the scorpion Androctonus mauretanicus mauretanicus, which is found in the Middle East and North Africa.

Chemistry

Kaliotoxin is a 4-kDa polypeptide chain containing 37 amino acids. The sequence has a large homology with iberiotoxin from "Buthus tumulus", charybdotoxin from "Leiurus quinquestriatus" and noxiustoxin from "Centruroides noxius".An Important site of the toxin is the K27 side chain (a lysine on place 27 of the protein sequence), which enters the pore and protrudes into the selectivity filter of the channel.

Target

KTX is a high affinity toxin, which binds to the Kv1.3 voltage-gated potassium channel and high conductance Calcium activated potassium channels (BK channels). These channels control several regulating processes, including neurotransmitter release, heart rate, insulin secretion, smooth muscle contraction.

Mode of action

The toxin binds to the potassium channel on the extracellular surface not voltage dependent. The configuration of the toxin fits onto the channel with the K27 side chain protruding into the pore and plugging it by conformational change of the toxin. The positively charged amino-group of the K27 chain fits into the selectivity filter near the G77 (Glycine) chain of the channel causing a conformational change of the channels selectivity filter. Thereby the hydrophobic groups of the K27 side chain replace water molecules in the entry region of the pore.So the pore is blocked by a direct plug into the pore region of the channel and a conformational change in the selectivity filter is induced.

Toxicity

References

1. High-resolution 3D structure determination of kaliotoxin by solid-state NMR spectroscopy. [http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002359 PLoS ONE. 2008 Jun 4;3(6):e2359]

2.The molecular mechanism of toxin-induced conformational changes in a potassium channel: relation to C-type inactivation. [http://www.structure.org/content/article/abstract?uid=PIIS0969212608000993 Structure. 2008 May;16(5):747-54]

3. Voltage-gated ion channels and gating modifier toxins. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCS-4M0H8CN-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=10&md5=07e4a758c5cdc9ef6cb48d5da59ce9e5 Toxicon. 2007 Feb;49(2):124-41]

4. Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR. [http://www.nature.com/nature/journal/v440/n7086/abs/nature04649.html Nature. 2006 Apr 13;440(7086):959-62]

5. Computational simulations of interactions of scorpion toxins with the voltage-gated potassium ion channel. [http://www.biophysj.org/cgi/content/full/86/6/3542 Biophys J. 2004 Jun;86(6):3542-55]

6. K(+) channels as therapeutic drug targets. Pharmacol Ther. 2002 Apr-May;94(1-2):157-82.

7. Structural Differences of Bacterial and Mammalian K1 Channels. [http://www.jbc.org/cgi/content/full/275/50/39345 J Biol Chem. 2000 Dec;275(50):39345-39353]

8. Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom. [http://www.jbc.org/cgi/reprint/267/3/1640 J Biol Chem. 1992 Jan 25;267(3):1640-7]