Abstract
cAMP is known to play an important role in insulin granule exocytosis from pancreatic β-cells. It is thought that the effects of cAMP on exocytosis are mediated by activation of cAMP-dependent protein kinase (PKA), a major target of cAMP, followed by phosphorylation of the proteins involved in insulin secretory process. We have previously found that cAMP sensor, cAMP-GEFII, is responsible for potentiation of cAMP-regulated, PKA-independent insulin granule exocytosis. The cAMP-GEFII-mediated insulin secretion requires the interaction of cAMP-GEFII with Piccolo as Ca2+ sensor and Rim2 as Rab3 effector. cAMP-GEFII also interacts with ATP sensor KATP channel through nucleotide-binding fold of SUR1, a subunit of KATP channel. Piccolo interacts with α11.2-subunit of L-type voltage-dependent Ca2+ channel (VDCC) in a Ca2+-independent manner. Piccolo also forms heterodimer with Rim2 as well as homodimer. These findings indicate that ATP sensor, cAMP sensor, and Ca2+ sensor interact with each other, thereby suggesting that intracellular signal such as ATP, cAMP, and Ca2+ in insulin granule exocytosis are integrated at a specialized region of pancreatic β-cell. cAMP signals are now known to be localized in distinct microdomains (or compartments) within a cell (cAMP compartmentation). cAMP-GEFII may reside in a cAMP compartment(s) distinct from those containing PKA compartment. In such a cAMP compartment of pancreatic β-cell, cAMP-GEFII specifically interacts with KATP channel, VDCC, and molecules associated with secretory vesicles, to facilitate stimulus-secretion coupling in insulin granule exocytosis. [Jpn J Physiol 55 Suppl:S34 (2005)]
