Molecular basis of K+ channel inactivation gating

The gating of many K+, Na+ and Ca++ channels is driven by changes in membrane potential. Part of the gating mechanism, the voltage sensing S4, a proposed transmembrane segment, has been identified. Movement in the membrane electric field of the charged S4 is thought to precede the opening and closing of the activation gate. The physical basis of the conformational changes involved in gating has yet to be elucidated. Here, we discuss a domain that appears to lie at the cytoplasmic mouth of K+ channels and to form a receptor for the inactivation gate. We examine the possibility that a) the physical attachment of this receptor/mouth to the S4 allows inactivation to be coupled to the voltage dependent conformational changes that open the channel and b) explains the immobilization of gating charge by inactivation. We also address the physiological ramifications of such structural coupling.