Coordinated Cross‐talk between calcium and cAMP in regulating pulsatile insulin secretion: A novel role for the unique inhibitory G‐protein, Gαz, in regulating β‐cell function

Abstract

Cyclic adenosine monophosphate (cAMP) is an important secondary messenger involved in a variety of signal transduction mechanisms. In the pancreatic β‐cell, cAMP amplifies pulsatile insulin secretion through protein kinase A (PKA) and the exchange protein activated by cAMP (EPAC). Inhibition of adenylyl cyclase (AC) limits glucose stimulated insulin secretion, even in the absence of activated stimulatory proteins, suggesting an essential role of cAMP in β‐cell function. It has been proposed that cAMP may coordinate with calcium oscillations to regulate pulsatile insulin secretion; however, this has not been demonstrated in intact islets under physiological conditions. In this study we utilize a β‐cell‐specific, genetically encoded cAMP biosensor expressed in intact isolated mouse islets to demonstrate for the first time an anti‐phasic relationship between cAMP and Ca2+ oscillations. This suggests that intracellular cAMP levels are governed by the Ca2+ sensitive phosphodiesterase, which act to degrade intracellular cAMP during the active phase of insulin exocytosis. Furthermore, loss of the inhibitory G‐protein alpha‐subunit, Gαz, an important contributor to diabetes pathology, increased the amplitude of cAMP oscillations and sensitivity to glucagon like peptide‐1 (GLP‐1) receptor stimulation. Ligand activation of E‐prostanoid receptor 3 (EP3), a G‐protein coupled receptor (GPCR) up regulated in the diabetic state that couples to Gαz, reduces cAMP oscillations but also dramatically blunts Ca2+ oscillations. These results suggest a coordinated cross‐talk between Ca2+ and cAMP dynamics in the β‐cell, as well as a novel role for Gz signaling which acts on both Ca2+ dynamics and inhibition of the cAMP‐mediated amplifying pathway of insulin secretion.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.