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Phosphorylation-dependent Functional Coupling of hSlo Calcium-dependent Potassium Channel and Its hβ4 Subunit*

P. Jin,T. Weiger,Yuying Wu,I. Levitan

Published 2002 in Journal of Biological Chemistry

ABSTRACT

The auxiliary β4 subunit of the humanslowpoke calciumdependent potassium (slo) channel is expressed predominantly in the brain. Co-expression of β4 subunit with the slo channel α subunit in HEK293 and Chinese hamster ovary cells slows channel activation and deactivation and also shifts the voltage dependence of the channel to more depolarized potentials. We show here that the functional interaction between the hβ4 subunit and theslo channel is influenced by the phosphorylation state of hβ4. Treatment of cells with okadaic acid (OA) reduces the effect of hβ4 on slo channel activation kinetics and voltage dependence but not on slo channel deactivation kinetics. The effect of OA can be blocked by mutating three putative serine/threonine phosphorylation sites in hβ4 (Thr-11/Ser-17/Ser-210) to alanines, suggesting that OA potentiates phosphorylation of hβ4 and thereby suppresses its functional coupling to the slochannel. Mutation of Ser-17 alone to a negatively charged residue (S17E) can mimic the effect of OA. Mutating all three phosphorylation sites in hβ4 to negatively charged residues (T11D/S17E/S210E) not only suppresses the effect of hβ4 on slo channel activation kinetics and voltage dependence, it also suppresses its effect on slo channel deactivation kinetics. Co-immunoprecipitation/Western blot experiments indicate that all of these hβ4 mutants, as well as the wild-type hβ4, bind to theslo channel. Taken together, these data suggest that phosphorylation of the β4 subunit dynamically regulates the functional coupling between the β4 subunit and the pore-forming α subunit of the slo channel. In addition, phosphorylation of different residues in hβ4 differentially influences its effects onslo channel activation kinetics, deactivation kinetics, and voltage dependence.

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