Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors

Xiaosong Ma, Yang Zhang, Jesper Gromada, Sabine Sewing, Per Olof Berggren, Karsten Buschard, Albert Salehi, Jenny Vikman, Patrik Rorsman, Lena Eliasson

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Glucagon, secreted by the pancreatic α-cells, stimulates insulin secretion from neighboring β-cells by CAMP- and protein kinase A (PKA)-dependent mechanisms, but it is not known whether glucagon also modulates its own secretion. We have addressed this issue by combining recordings of membrane capacitance (to monitor exocytosis) in individual α-cells with biochemical assays of glucagon secretion and cAMP content in intact pancreatic islets, as well as analyses of glucagon receptor expression in pure α-cell fractions by RT-PCR. Glucagon stimulated cAMP generation and exocytosis dose dependently with an EC50 of 1.6-1.7 nM. The stimulation of both parameters plateaued at concentrations beyond 10 nM of glucagon where a more than 3-fold enhancement was observed. The actions of glucagon were unaffected by the GLP-1 receptor antagonist exendin-(9-39) but abolished by des-His 1-[Glu9]-glucagonamide, a specific blocker of the glucagon receptor. The effects of glucagon on α-cell exocytosis were mimicked by forskolin and the stimulatory actions of glucagon and forskolin on exocytosis were both reproduced by intracellular application of 0.1 mM cAMP. cAMP-potentiated exocytosis involved both PKA-dependent and -independent (resistant to Rp-cAMPS, an Rp-isomer of cAMP) mechanisms. The presence of the cAMP-binding protein cAMP-guanidine nucleotide exchange factor II in α-cells was documented by a combination of immunocytochemistry and RT-PCR and 8-(4-chloro-phenylthio)-2′-O-methyl-cAMP, a cAMP-guanidine nucleotide exchange factor II-selective agonist, mimicked the effect of cAMP and augmented rapid exocytosis in a PKA-independent manner. We conclude that glucagon released from the α-cells, in addition to its well-documented systemic effects and paracrine actions within the islet, also represents an autocrine regulator of α-cell function.

Original languageEnglish
Pages (from-to)198-212
Number of pages15
JournalMolecular Endocrinology
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

Fingerprint

Glucagon Receptors
Exocytosis
Glucagon
Cyclic AMP-Dependent Protein Kinases
Guanidine
Colforsin
Nucleotides
Polymerase Chain Reaction
Islets of Langerhans
Carrier Proteins
Immunohistochemistry
Insulin

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Ma, X., Zhang, Y., Gromada, J., Sewing, S., Berggren, P. O., Buschard, K., ... Eliasson, L. (2005). Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors. Molecular Endocrinology, 19(1), 198-212. https://doi.org/10.1210/me.2004-0059

Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors. / Ma, Xiaosong; Zhang, Yang; Gromada, Jesper; Sewing, Sabine; Berggren, Per Olof; Buschard, Karsten; Salehi, Albert; Vikman, Jenny; Rorsman, Patrik; Eliasson, Lena.

In: Molecular Endocrinology, Vol. 19, No. 1, 01.01.2005, p. 198-212.

Research output: Contribution to journalArticle

Ma, X, Zhang, Y, Gromada, J, Sewing, S, Berggren, PO, Buschard, K, Salehi, A, Vikman, J, Rorsman, P & Eliasson, L 2005, 'Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors', Molecular Endocrinology, vol. 19, no. 1, pp. 198-212. https://doi.org/10.1210/me.2004-0059
Ma, Xiaosong ; Zhang, Yang ; Gromada, Jesper ; Sewing, Sabine ; Berggren, Per Olof ; Buschard, Karsten ; Salehi, Albert ; Vikman, Jenny ; Rorsman, Patrik ; Eliasson, Lena. / Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors. In: Molecular Endocrinology. 2005 ; Vol. 19, No. 1. pp. 198-212.
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