1. Department of Physiology, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA

Correspondence to: Zhe Lu¹ Correspondence and requests for materials should be addressed to Z.L. (Email: zhelu@mail.med.upenn.edu).

Abstract

A fundamental question about the gating mechanism of voltage-activated K⁺ (Kv) channels is how five positively charged voltage-sensing residues^{1, 2} in the fourth transmembrane segment are energetically stabilized, because they operate in a low-dielectric cell membrane. The simplest solution would be to pair them with negative charges³. However, too few negatively charged channel residues are positioned for such a role^{4, 5}. Recent studies suggest that some of the channel's positively charged residues are exposed to cell membrane phospholipids and interact with their head groups^{5, 6, 7, 8, 9}. A key question nevertheless remains: is the phospho-head of membrane lipids necessary for the proper function of the voltage sensor itself? Here we show that a given type of Kv channel may interact with several species of phospholipid and that enzymatic removal of their phospho-head creates an insuperable energy barrier for the positively charged voltage sensor to move through the initial gating step(s), thus immobilizing it, and also raises the energy barrier for the downstream step(s).

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