Abstract
Small-conductance Ca
2+
-activated K
+
(SK) channels are a unique group of K
+
channels, that play important roles in the vascular system and central nervous system. Four subtypes in the SK channel family are encoded by
KCNN
mammalian genes: including
KCNN1
for SK1 (K
Ca
2.1),
KCNN2
for SK2 (K
Ca
2.2),
KCNN3
for SK3 (K
Ca
2.3) and
KCNN4
for SK4 (also IK or K
Ca
3.1) channels. It is well known that the activation of SK channels expressed on the endothelial cell surface can reduce vascular tone. In our study, we found that SK channels expressed on the endoplasmic reticulum (ER) membrane can protect endothelial cells from apoptosismediated by ER stress. Among the four subtypes of SK channels, Ca
2+
sensitivity and subcellular localization significantly varies by subtype in endothelial cells. Ca
2+
sensitivity of the SK1 channel subtype is negatively modulated more than that of the SK2 subtype, whereas the cell surface expression of the SK2 channel subtype is negatively modulated more than that of the SK1 subtype. The functions of SK channels to reduce vascular tone and to protect against apoptosis are greatly affected by their Ca
2+
sensitivity and subcellular localization. It is critical to understand how each SK channel subtype is modulated, which may become promising therapeutic targets for various cardiovascular conditions.