Structural Insights into the Mechanisms and Pharmacology of K(2P) Potassium Channels

Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K(2P) (KCNK) potassium channel class comprises an ion channel family that produces potassium leak currents that oppose excitation and stabilize the resting membrane potential in cells in the brain, cardiovascular system, immune system, and sensory organs. Due to their widespread tissue distribution, K(2P)s contribute to many physiological and pathophysiological processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Structural studies of six homomeric K(2P)s have established the basic architecture of this channel family, revealed key moving parts involved in K(2P) function, uncovered the importance of asymmetric pinching and dilation motions in the K(2P) selectivity filter (SF) C-type gate, and defined two K(2P) structural classes based on the absence or presence of an intracellular gate. Further, a series of structures characterizing K(2P):modulator interactions have revealed a striking polysite pharmacology housed within a relatively modestly sized (~70 kDa) channel. Binding sites for small molecules or lipids that control channel function are found at every layer of the channel structure, starting from its extracellular side through the portion that interacts with the membrane bilayer inner leaflet. This framework provides the basis for understanding how gating cues sensed by different channel parts control function and how small molecules and lipids modulate K(2P) activity. Such knowledge should catalyze development of new K(2P) modulators to probe function and treat a wide range of disorders.