The Pharmacology of Two-Pore Domain Potassium Channels

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 K_2P subunits were identified in the human genome. The human K_2P channels are stratified into six K_2P subfamilies based on sequence as well as physiological or pharmacological similarities. Functional K_2P 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 K_2P channel gating in response to specific physicochemical or pharmacological stimuli. The growing appreciation that K_2P channels can play a pivotal role in the pathophysiology of a growing spectrum of diseases makes a compelling case for K_2P channels as targets for drug discovery. Here, we summarize recent advances in unraveling the structure, function, and pharmacology of the K₂P channels.