SKA-31

Ca²⁺-activated potassium channels (K_Ca) are a group of 6/7-TM proteins that selectively transport K⁺ ions across biological membranes. They are broadly classified into three subtypes: SK, IK and BK channels (small, intermediate and big conductance, respectively). The three small-conductance Ca²⁺-activated K⁺ channels K_Ca2.1 (SK1), K_Ca2.2 (SK2), and K_Ca2.3 (SK3)¹, and the intermediate-conductance K_Ca3.1 channel (IK1, SK4) play important roles in various physiological functions by modulating Ca²⁺-signaling cascades and regulating membrane potential, in the CNS and also peripherally^1-2.

Outside of the nervous system K_Ca2 channels, especially K_Ca2.3, are involved in blood pressure regulation³, contractility of urinary bladder smooth muscle and metabolism⁴. Like K_Ca2.3, K_Ca3.1 is further expressed in vascular endothelium and contributes to blood pressure control by initiating the so-called endothelium derived hyperpolarizing factor (EDHF) response, a nitric oxide and prostacyclin independent component of endothelium-dependent relaxation^5-9.

SKA-31 is an activator of K_Ca3.1 and K_Ca2 channels (EC₅₀ values are 260, 2900, 2900, 1900 nM for K_Ca3.1, K_Ca2.1, K_Ca2.3 and K_Ca2.2 respectively)¹⁰. It potentiates acetylcholine-induced EDHF-type dilations of mouse carotid arteries and lowers blood pressure in normotensive and hypertensive mice, by 4-6 and 12 mmHg, respectively^10-11.

SKA-31 was found to block TRPM7 channels, demonstrating an overlap between pharmacological compounds acting on TRP and K_Ca channels¹².