Calmodulin regulates assembly and trafficking of SK4/IK1 Ca2+-activated K+channels

Calmodulin (CaM) regulates gating of several types of ion channels but has not been implicated in channel assembly or trafficking. For the SK4/IK1 Kchannel, CaM bound to the proximal C terminus ("Ct1 " domain) acts as the C a2+ sensor. We now show that CaM interacting with the C terminus of SK4 als o controls channel assembly and surface expression. In transfected cells, r emoving free CaM by overexpressing the CaM-binding domain, Ct1, redistribut ed full-length SK4 protein from the plasma membrane to the cytoplasm and de creased whole-cell currents. Making more CaM protein available by overexpre ssing the CaM gene abrogated the dominant-negative effect of Ct1 and restor ed both surface expression of SK4 protein and whole-cell currents. The dist al C-terminal domain ("Ct2") also plays a role in assembly, but is not CaM- dependent. Co-immunoprecipitation experiments demonstrated that multimeriza tion of SK4 subunits was enhanced by CaM and inhibited by removal of CaM, i ndicating that CaM regulates trafficking of SK4 by affecting the assembly o f channels. Our results support a model in which CaM-dependent association of SK4 monomers at their Ct1 domains regulates channel assembly and surface expression. This appears to represent a novel mechanism for controlling io n channels, and consequently, the cellular functions that depend on them.