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Br J Pharmacol. 2010 Apr;159(7):1475-85. doi: 10.1111/j.1476-5381.2010.00642.x. Epub 2010 Feb 5.

Inhalational anaesthetics and n-alcohols share a site of action in the neuronal Shaw2 Kv channel.

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  • 1Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.

Abstract

BACKGROUND AND PURPOSE:

Neuronal ion channels are key targets of general anaesthetics and alcohol, and binding of these drugs to pre-existing and relatively specific sites is thought to alter channel gating. However, the underlying molecular mechanisms of this action are still poorly understood. Here, we investigated the neuronal Shaw2 voltage-gated K(+) (K(v)) channel to ask whether the inhalational anaesthetic halothane and n-alcohols share a binding site near the activation gate of the channel.

EXPERIMENTAL APPROACH:

Focusing on activation gate mutations that affect channel modulation by n-alcohols, we investigated n-alcohol-sensitive and n-alcohol-resistant K(v) channels heterologously expressed in Xenopus oocytes to probe the functional modulation by externally applied halothane using two-electrode voltage clamping and a gas-tight perfusion system.

KEY RESULTS:

Shaw2 K(v) channels are reversibly inhibited by halothane in a dose-dependent and saturable manner (K(0.5)= 400 microM; n(H)= 1.2). Also, discrete mutations in the channel's S4S5 linker are sufficient to reduce or confer inhibition by halothane (Shaw2-T330L and K(v)3.4-G371I/T378A respectively). Furthermore, a point mutation in the S6 segment of Shaw2 (P410A) converted the halothane-induced inhibition into halothane-induced potentiation. Lastly, the inhibition resulting from the co-application of n-butanol and halothane is consistent with the presence of overlapping binding sites for these drugs and weak binding cooperativity.

CONCLUSIONS AND IMPLICATIONS:

These observations strongly support a molecular model of a general anaesthetic binding site in the Shaw2 K(v) channel. This site may involve the amphiphilic interface between the S4S5 linker and the S6 segment, which plays a pivotal role in K(v) channel activation.

PMID:
20136839
PMCID:
PMC2850404
DOI:
10.1111/j.1476-5381.2010.00642.x
[PubMed - indexed for MEDLINE]
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