Up-Regulation of the Large-Conductance Ca ²⁺ -Activated K ⁺ Channel by Glycogen Synthase Kinase GSK3β

Background/Aims: The pleotropic functions of the large conductance Ca ²⁺ -activated K ⁺ channels (maxi K ⁺ channel or BK channels) include regulation of neuronal excitation and cell volume. Kinases participating in those functions include the glycogen synthase kinase GSK3 ß which is under negative control of protein kinase B (PKB/Akt). GSK3ß is inhibited by the antidepressant Lithium. The present study thus explored whether GSK3ß modifies the activity of BK channels. Methods: cRNA encoding the Ca ²⁺ insensitive BK channel mutant BK ^{M513I+Δ899-903} was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding wild-type GSK3ß, inactive ^K85R GSK3ß, or wild-type GSK3ß with wild-type PKB. K ⁺ channel activity was measured utilizing dual electrode voltage clamp. Results: BK channel activity in BK ^{M513I+Δ899-903} expressing oocytes was significantly increased by co-expression of GSK3ß, but not by co-expression of ^K85R GSK3ß. The effect of wild type GSK3ß was abrogated by additional co-expression of wild-type PKB and by 24 hours incubation with Lithium (1 mM). Disruption of channel insertion into the cell membrane by brefeldin A (5 μM) was followed by a decline of the current to a similar extent in oocytes expressing BK and GSK3ß and in oocytes expressing BK alone. Conclusion: GSK3ß may up-regulate BK channels, an effect disrupted by Lithium or additional expression of PKB and possibly participating in the regulation of cell volume and excitability.