The adenylyl cyclase inhibitor MDL-12,330A potentiates insulin secretion via blockade of voltage-dependent K(+) channels in pancreatic beta cells

Objective: Adenylyl cyclases (ACs) play important role in regulating pancreatic beta cell growth, survival and secretion through the synthesis of cyclic AMP (cAMP). MDL-12,330A and SQ 22536 are two AC inhibitors used widely to establish the role of ACs. The goal of this study was to examine the effects of MDL-12,330A and SQ 22536 on Insulin secretion and underlying mechanisms.

Methods: Patch-clamp recording, CA(2+) fluorescence imaging and radioimmunoassay were used to measure outward K(+) currents, action potentials (APs), intracellular CA(2+) ([CA(2+)]i) and Insulin secretion from rat pancreatic beta cells.

Results: MDL-12,330A (10 µmol/l) potentiated Insulin secretion to 1.7 times of control in the presence of 8.3 mmol/l glucose, while SQ 22536 did not show significant effect on Insulin secretion. MDL-12,330A prolonged AP durations (APDs) by inhibiting voltage-dependent K(+) (KV) channels, leading to an increase in [CA(2+)]i levels. It appeared that these effects induced by MDL-12,330A did not result from AC inhibition, since SQ 22536 did not show such effects. Furthermore, inhibition of the downstream effectors of AC/cAMP signaling by PKA Inhibitor H89 and Epac inhibitor ESI-09, did not affect KV channels and Insulin secretion.

Conclusion: The putative AC inhibitor MDL-12,330A enhances [CA(2+)]i and Insulin secretion via inhibition of KV channels rather than AC antagonism in beta cells, suggesting that the non-specific effects is needed to be considered for the right interpretation of the experimental results using this agent in the analyses of the role of AC in cell function.