GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis.
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).
Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SE20502 Malmö, Sweden.
Yang Z
YZ
De Marinis
Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SE20502 Malmö, Sweden.
Albert
A
Salehi
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Caroline E
CE
Ward
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Quan
Q
Zhang
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.|Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, 05508-00 São Paulo, Brazil.
Fernando
F
Abdulkader
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Martin
M
Bengtsson
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Orit
O
Braha
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Matthias
M
Braun
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Reshma
R
Ramracheya
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Stefan
S
Amisten
Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0XY, UK.
Abdella M
AM
Habib
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Yusuke
Y
Moritoh
Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SE20502 Malmö, Sweden.
Enming
E
Zhang
Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0XY, UK.
Frank
F
Reimann
Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SE20502 Malmö, Sweden.
Anders
A
Rosengren
Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
Tadao
T
Shibasaki
Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0XY, UK.
Fiona
F
Gribble
Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SE20502 Malmö, Sweden.
Erik
E
Renström
Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
Susumu
S
Seino
Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SE20502 Malmö, Sweden.
Lena
L
Eliasson
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Patrik
P
Rorsman
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004837:Epinephrine / Q000378:metabolism*; D005089:Exocytosis; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL
D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; C486707:Rapgef4 protein, mouse; D005576:Colforsin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine