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This Article Full Text Full Text (PDF) All Versions of this Article: 559/2/397    most recent jphysiol.2004.066563v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Braun, M. Articles by Rorsman, P. Search for Related Content PubMed PubMed Citation Articles by Braun, M. Articles by Rorsman, P.

¹ Department of Physiological Sciences, BMC B11, SE-221 84 Lund, Sweden
² Bartholin Instituttet, Kommunehospitalet, DK-1399 Copenhagen, Denmark
³ Lilly Research Laboratories, Essener Strasse 93, D-22419 Hamburg, Germany
⁴ The Oxford Centre for Diabetes, Endocrinology and Metabolism, the Churchill Hospital, Oxford OX3 7LJ, UK

We have investigated the regulation of hormone secretion from rat pancreatic islets by the GABA_B receptors (GABA_BRs). Inclusion of the specific GABA_BR 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 GABA_BR agonist baclofen inhibited glucose-stimulated insulin secretion by 60%. Using RT-PCR, transcription of GABA_BR_1a-c,f and GABA_BR₂ subunits was detected in ß-cells. Measurements of membrane currents and cell capacitance were applied to single ß-cells to investigate the mechanisms by which GABA_BR activation inhibits insulin secretion. In perforated-patch measurements, baclofen inhibited exocytosis elicited by 500-ms voltage-clamp depolarizations to 0 mV by 80% and voltage-gated Ca²⁺ entry by only 30%. Both effects were concentration-dependent with IC₅₀ values of 2 µM. The inhibitory action of baclofen was abolished in the presence of CGP 55845. The ability of baclofen to suppress exocytosis was prevented by pre-treatment with pertussis toxin and by inclusion of GDPßS in the intracellular medium, and became irreversible in the presence of GTPS as expected for a process involving inhibitory G-proteins (G_i/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 abolished the effect. Addition of baclofen had no effect on [Ca²⁺]_i and electrical activity in glucose-stimulated ß-cells. These data indicate that GABA released from ß-cells functions as an autocrine inhibitor of insulin secretion in pancreatic islets and that the effect is principally due to direct suppression of exocytosis.

(Received 14 April 2004; accepted after revision 25 June 2004; first published online 2 July 2004)
Corresponding author M. Braun: Department of Physiological Sciences, BMC B11, SE-221 84 Lund, Sweden. Email: matthias.braun{at}mphy.lu.se

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