Glucagon induces suppression of ATP-sensitive K+ channel activity through a Ca2+/calmodulin-dependent pathway in mouse pancreatic beta-cells

Glucagon is known to increase intracellular cAMP levels and enhance glucose -induced electrical activity and insulin secretion in pancreatic beta-cell perfused with Krebs-Ringer bicarbonate solution. The present experiments we re aimed at evaluation of the hypothesis that changes in beta-cells ATP-sen sitive K+ (K-(ATP)) channel activity are involved in the glucagon-induced e nhancement of electrical activity. Channel activity was recorded using the cell-attached configuration of the patch-clamp technique. Addition of gluca gon (2.9 x 10(-7) M) in the presence of 11.1 mM glucose caused closure of K -(ATP) channels followed by an increase in the frequency of biphasic curren t transients (action currents) due to action potential generation in the ce ll. Three calmodulin-antagonists (W-7, chlorpromazine, and trifluoperazine) restored with similar efficacy K-(ATP) channel activity in cells being exp osed to glucagon. At 2.8 mM glucose, glucagon did not affect K-(ATP) channe l activity until Ca2+ was released from Nitr-5 by flash photolysis, at whic h point channel activity was transiently suppressed. Similar effects were s een when db-cAMP was used instead of glucagon. These results support the vi ew that glucagon and other cAMP-generating agonists enhance glucose-induced beta-cell electrical activity through a Ca2+/calmodulin dependent-closure of K-(ATP) channels.