Crosstalk Between Calcium and cAMP in Pancreatic Alpha Cells

Abstract

Glucagon secretion from pancreatic alpha cells can be controlled by a variety of factors including hypoglycemia-induced increase in calcium or by hormones that stimulate cAMP production. The mechanisms by which calcium and cAMP signals influence each other and glucagon secretion have yet to be resolved. Using fura2 imaging, we found that acute hypoglycemia-triggered calcium-induced calcium release (CICR) in clonal mouse alpha cells was sensitive to the calcium channel blockers, nifedipine and w-conotoxin-GVIA. CICR with similar channel pharmacology was triggered by forskolin-induced elevation of [cAMP] revealing cAMP-stimulation of [Ca2+]i. This CICR likely involved multiple cAMP targets as both PKA-selective and EPAC-selective cAMP analogs each triggered CICR. In addition, a role for calcium regulation of [cAMP] was revealed by hypoglycemia-triggered increase in [cAMP] as reported by imaging of an EPAC-based cAMP FRET indicator. This was presumably due to calcium regulation of adenylyl cyclase or cAMP phosphodiesterase (PDE). Multiple isoforms of adenylyl cyclase and PDEs including Ca-sensitive AC3 and PDE1 were detected by RT-PCR in alpha cells. PDE3- and PDE4-selective inhibitors had distinct effects on calcium and cAMP dynamics and whole cell calcium currents. These data suggest multiple points of cAMP and calcium crosstalk in regulating glucagon secretion.