GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis
Yang Z De Marinis, Albert Salehi, Caroline E Ward, Quan Zhang, Fernando Abdulkader, Martin Bengtsson, Orit Braha, Matthias Braun, Reshma Ramracheya, Stefan Amisten, Abdella M Habib, Yusuke Moritoh, Enming Zhang, Frank Reimann, Anders Rosengren, Tadao Shibasaki, Fiona Gribble, Erik Renström, Susumu Seino, Lena Eliasson, Patrik Rorsman, Yang Z De Marinis, Albert Salehi, Caroline E Ward, Quan Zhang, Fernando Abdulkader, Martin Bengtsson, Orit Braha, Matthias Braun, Reshma Ramracheya, Stefan Amisten, Abdella M Habib, Yusuke Moritoh, Enming Zhang, Frank Reimann, Anders Rosengren, Tadao Shibasaki, Fiona Gribble, Erik Renström, Susumu Seino, Lena Eliasson, Patrik Rorsman
Abstract
Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 muM) concentrations of forskolin, respectively. The expression of GLP-1 receptors in alpha cells is <0.2% of that in beta cells. The GLP-1-induced suppression of glucagon secretion is PKA dependent, is glucose independent, and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on alpha cell electrical activity but selectively inhibits N-type Ca(2+) channels and exocytosis. Adrenaline stimulates alpha cell electrical activity, increases [Ca(2+)](i), enhances L-type Ca(2+) channel activity, and accelerates exocytosis. The stimulatory effect is partially PKA independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca(2+) channels via a small increase in intracellular cAMP ([cAMP](i)). Adrenaline stimulates L-type Ca(2+) channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP](i).
Copyright 2010 Elsevier Inc. All rights reserved.
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Source: PubMed