K₂P Channels as Key Regulators of Cardiovascular and Pulmonary Vascular Function

Two-pore domain potassium (K₂P) channels are the most recently identified family of potassium channels. They are regarded as the largest group of background "leak" channels, encoded by 15 mammalian KCNK genes, and divided into six subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). These channels have a role in stabilizing the resting membrane potential. Their widespread presence in the heart and vasculature supports cellular homeostasis by regulating cardiac rhythm, vascular tone, and protection against ischemic stress. The TASK, TWIK, and TREK subfamilies are the most abundantly expressed K₂P channel subfamilies in the cardiovascular system, and dysregulation of specific members has been strongly linked to the development of major cardiovascular diseases. Mutations in TASK-1 have been identified in patients with pulmonary arterial hypertension, providing human genetic evidence linking K₂P dysfunction to pulmonary vascular disease. While alterations in other K₂P channels, such as TREK-1, have been demonstrated in preclinical studies where reduced channel activity is associated with ischemia-reperfusion injury and promotes cardiac arrhythmias. Growing evidence suggests that K₂P channels could serve as promising therapeutic targets, with pharmacological activation of TASK-1 and TREK-1, for instance, that might help restore vascular tone, reduce remodeling, and offer cardioprotection. Their unique leak-channel properties enable the development of highly selective treatments. This review addresses the molecular biology, physiological roles, and disease relevance of K₂P channels in the cardiovascular and pulmonary systems, emphasizing their potential as targets for innovative therapies in cardiovascular diseases.