Two-Pore-Domain Potassium Channels

Physiologists have appreciated the importance of background (or leak) K⁺ currents in determining the cellular resting membrane potential (V_M) from the early 1900s. Since then, the activity of background K⁺ fluxes have been shown to regulate many aspects of cellular electrophysiology, including the shape and frequency of action potentials in neurons and cardiomyocytes, and the control of K⁺ homeostasis and endocrine function in epithelial and secretory tissues. It was not until the mid-1990s that the genes for K⁺ channels with the biophysical attributes of native background currents were cloned, expressed and studied. In higher-order eukaryotes, background channels are built from K2P subunits that are distinguished by four-transmembrane domains and two-pore forming loops. Humans express K2P subunits from 15 genes. The channels are assembled as subunit homodimers or heterodimers that create a single, K⁺ ion-selective conduction pathway, which is active across physiological voltages. Here, we describe the structure and function of K2P channels with an emphasis on their contributions to physiology, pathophysiology and pharmacology.