Modulation of endothelial SK3 channel activity by Ca~(2+)-dependent caveolar trafficking

摘要

Small- and intermediate-conductance Ca~(2+)-activated K~+ channels (SK3/Kcnn3 and IK1/Kcnn4) are expressed in vascular endothelium. Their activities play important roles in regulating vascular tone through their modulation of intracellular concentration ([Ca~(2+)]_i) required for the production of endothelium-derived vasoactive agents. Activation of endothelial IK1 or SK3 channels hyperpolarizes endothelial cell membrane potential, increases Ca~(2+) influx, and leads to the release of vasoactive factors, thereby impacting blood pressure. To examine the distinct roles of IK1 and SK3 channels, we used electro-physiological recordings to investigate IK1 and SK3 channel trafficking in acutely dissociated endothelial cells from mouse aorta. The results show that SK3 channels undergo Ca~(2+)-dependent cycling between the plasma membrane and intracellular organelles; disrupting Ca~(2+)-depen-dent endothelial caveolae cycling abolishes SK3 channel trafficking. Moreover, transmitter-induced changes in SK3 channel activity and surface expression modulate endothelial membrane potential. In contrast, IK1 channels do not undergo rapid trafficking and their activity remains unchanged when either exo- or endocytosis is block. Thus modulation of SK3 surface expression may play an important role in regulating endothelial membrane potential in a Ca~(2+)-dependent manner.