Therapeutic targeting of two-pore-domain potassium (K_2P) channels in the cardiovascular system

The improvement of treatment strategies in cardiovascular medicine is an ongoing process that requires constant optimization. The ability of a therapeutic intervention to prevent cardiovascular pathology largely depends on its capacity to suppress the underlying mechanisms. Attenuation or reversal of disease-specific pathways has emerged as a promising paradigm, providing a mechanistic rationale for patient-tailored therapy. Two-pore-domain K⁺ (K_2P) channels conduct outward K⁺ currents that stabilize the resting membrane potential and facilitate action potential repolarization. K_2P expression in the cardiovascular system and polymodal K_2P current regulation suggest functional significance and potential therapeutic roles of the channels. Recent work has focused primarily on K_2P1.1 [tandem of pore domains in a weak inwardly rectifying K⁺ channel (TWIK)-1], K_2P2.1 [TWIK-related K⁺ channel (TREK)-1], and K_2P3.1 [TWIK-related acid-sensitive K⁺ channel (TASK)-1] channels and their role in heart and vessels. K_2P currents have been implicated in atrial and ventricular arrhythmogenesis and in setting the vascular tone. Furthermore, the association of genetic alterations in K_2P3.1 channels with atrial fibrillation, cardiac conduction disorders and pulmonary arterial hypertension demonstrates the relevance of the channels in cardiovascular disease. The function, regulation and clinical significance of cardiovascular K_2P channels are summarized in the present review, and therapeutic options are emphasized.