Abstract
First identified 40 years ago in cardiac myocytes, ATP-sensitive potassium (K(ATP)) channels have been found in almost all excitable tissues, with paradigmatic inhibition by ATP and activation by ADP underlying their physiological role in coupling cellular metabolism to electrical activity. Cloning of the underlying genes, 30 years ago, revealed their unique assembly as four Kir6.x pore-forming subunit proteins and four sulfonylurea receptor (SURx) subunit proteins and has since led to discovery of a spectrum of monogenic diseases resulting from gain- (GOF) or loss-of-function (LOF) mutations, in turn leading to recognition of novel physiological roles and pathophysiological consequences throughout the body. With this perspective, this lecture represents a personal view of these discoveries and the potential for future pathophysiological insights.