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First published online on July 2, 2004.
 Copyright © 2004 by The Physiological Society
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Received April 14, 2004
Revised May 7, 2004
Accepted after revision June 25, 2004

GABAB-receptor activation inhibits exocytosis in rat pancreatic {beta}-cells by G-protein-dependent activation of calcineurin

Matthias Braun1*, Anna Wendt1, Karsten Buschard2, Albert Salehi1, Sabine Sewing3, Jesper Gromada3, and Patrik Rorsman1

1 Lund University
2 Kommunehospitalet Copenhagen
3 Lilly Research Laboratories Hamburg

* To whom correspondence should be addressed. E-mail: matthias.braun{at}mphy.lu.se.

We have investigated the regulation of hormone secretion from rat pancreatic islet by GABAB-receptors (GABABR). Inclusion of the GABABR antagonist CGP 55845 in the extracellular medium increased glucose-stimulated insulin secretion 1.6-fold but did not affect the release of glucagon and somatostatin. Conversely, addition of the GABABR agonist baclofen inhibited glucose-stimulated insulin secretion by {approx}60%. Using RT-PCR, transcription of GABABR1a-c,f and GABABR2 was detected in {beta}-cells. Measurements of membrane currents and cell capacitance were applied to single {beta}-cells to investigate the mechanisms by which GABABR activation inhibits insulin secretion. In perforated-patch measurements, baclofen inhibited exocytosis elicited by 500-ms voltage-clamp depolarisations to zero mV by ≤80% and voltage-gated Ca2+ entry by only {approx}30%. Both effects were concentration-dependent with IC50-values of {approx}2 µM. The inhibitory action of baclofen was abolished in the presence of the specific GABABR antagonist CGP 55845. The ability of baclofen to suppress exocytosis was prevented by pre-treatment with pertussis toxin and by inclusion of 0.5 mM GDP{beta}S in the intracellular medium and became irreversible in the presence of GTP{gamma}S as expected for a process involving Gi/o-proteins. The inhibitory effect of baclofen resulted from activation of the serine/threonine protein phosphatase calcineurin and pre-treatment with cyclosporin A or intracellular application of calcineurin autoinhibitory peptide prevented the effects. Addition of baclofen had no effect on [Ca2+]i and electrical activity in glucose-stimulated {beta}-cells. These data indicate that GABA released from {beta}-cells functions as an autocrine inhibitor of insulin secretion in pancreatic islets and that the effect is principally due to direct suppression of exocytosis.


Key words: Exocytosis • GABA receptor • Pancreatic Β-cell




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