Key result
Structural studies of K2P potassium channels have revealed their core architecture, unique gating mechanisms, and a rich polysite pharmacology that provides a basis for developing new modulators.
Structural insights into K2P potassium channels reveal a complex polysite pharmacology and distinct gating mechanisms, providing a foundation for developing novel therapeutics for conditions including arrhythmias and ischemia.
May guide K2P modulator development for arrhythmias; leaves open clinical translation pending validation.
Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K2P (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, K2Ps 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 K2Ps have established the basic architecture of this channel family, revealed key moving parts involved in K2P function, uncovered the importance of asymmetric pinching and dilation motions in the K2P selectivity filter (SF) C-type gate, and defined two K2P structural classes based on the absence or presence of an intracellular gate. Further, a series of structures characterizing K2P: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 K2P activity. Such knowledge should catalyze development of new K2P modulators to probe function and treat a wide range of disorders.
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Natale et al. (2021) conducted a review in K2P Potassium Channel function and pharmacology. Structural studies of K2P potassium channels have revealed their core architecture, unique gating mechanisms, and a rich polysite pharmacology that provides a basis for developing new modulators.
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