Differential modulation of SK channel subtypes by phosphorylation

[Display omitted] •CK2 inhibitors caused changes greater than 5-fold in the apparent Ca2+ sensitivity of the SK1 and IK channel subtypes.•CK2 inhibitors induced only ∼2-fold changes in the apparent Ca2+ sensitivity of the SK2 and SK3 channel subtypes.•The SK2 channel subtype expresses on the ER membrane more abundantly than on the plasma membrane.•The limited SK2 expression on the plasma membrane may be related at least partly to its phosphorylation by PKA.•SK2 channels expressed on the intracellular membranes may protect endothelial cells against palmitate-induced cell death. Small-conductance Ca2+-activated K+ (SK) channels are voltage-independent and are activated by Ca2+ binding to the calmodulin constitutively associated with the channels. Both the pore-forming subunits and the associated calmodulin are subject to phosphorylation. Here, we investigated the modulation of different SK channel subtypes by phosphorylation, using the cultured endothelial cells as a tool. We report that casein kinase 2 (CK2) negatively modulates the apparent Ca2+ sensitivity of SK1 and IK channel subtypes by more than 5-fold, whereas the apparent Ca2+ sensitivity of the SK3 and SK2 subtypes is only reduced by ∼2-fold, when heterologously expressed on the plasma membrane of cultured endothelial cells. The SK2 channel subtype exhibits limited cell surface expression in these cells, partly as a result of the phosphorylation of its C-terminus by cyclic AMP-dependent protein kinase (PKA). SK2 channels expressed on the ER and mitochondria membranes may protect against cell death. This work reveals the subtype-specific modulation of the apparent Ca2+ sensitivity and subcellular localization of SK channels by phosphorylation in cultured endothelial cells.