The Pharmacology of Two-Pore Domain Potassium Channels.

Abstract

Two-pore domain potassium channels are formed by subunits that each contain two pore-loops moieties. Whether the channels are expressed in yeast or the human central nervous system, two subunits come together to form a single potassium selective pore. TOK1, the first two-domain channel was cloned from Saccharomyces cerevisiae in 1995 and soon thereafter, 15 distinct K2P subunits were identified in the human genome. The human K2P channels are stratified into six K2P subfamilies based on sequence as well as physiological or pharmacological similarities. Functional K2P channels pass background (or "leak") K+ currents that shape the membrane potential and excitability of cells in a broad range of tissues. In the years since they were first described, classical functional assays, latterly coupled with state-of-the-art structural and computational studies have revealed the mechanistic basis of K2P channel gating in response to specific physicochemical or pharmacological stimuli. The growing appreciation that K2P channels can play a pivotal role in the pathophysiology of a growing spectrum of diseases makes a compelling case for K2P channels as targets for drug discovery. Here, we summarize recent advances in unraveling the structure, function, and pharmacology of the K2P channels.