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GABAB-receptor acti...
GABAB-receptor activation inhibits exocytosis in rat pancreatic {beta}-cells by G-protein-dependent activation of calcineurin.
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- Braun, Matthias (författare)
- Lund University,Lunds universitet,Islet cell physiology,Forskargrupper vid Lunds universitet,Lund University Research Groups
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- Wendt, Anna (författare)
- Lund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups
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Buschard, Karsten (författare)
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Salehi, Albert (författare)
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Sewing, Sabine (författare)
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Gromada, Jesper (författare)
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- Rorsman, Patrik (författare)
- Lund University,Lunds universitet,Islet cell physiology,Forskargrupper vid Lunds universitet,Lund University Research Groups
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(creator_code:org_t)
- 2004-08-25
- 2004
- Engelska.
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Ingår i: Journal of Physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 559:2, s. 397-409
- Relaterad länk:
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http://www.ncbi.nlm.... (free)
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http://dx.doi.org/10... (free)
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https://physoc.onlin...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- We have investigated the regulation of hormone secretion from rat pancreatic islets by the GABAB receptors (GABABRs). Inclusion of the specific 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 ∼60%. Using RT-PCR, transcription of GABABR1a-c,f and GABABR2 subunits was detected in β-cells. Measurements of membrane currents and cell capacitance were applied to single β-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 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 GDPβS in the intracellular medium, and became irreversible in the presence of GTPγS as expected for a process involving inhibitory G-proteins (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 abolished the effect. Addition of baclofen had no effect on [Ca2+]i and electrical activity in glucose-stimulated β-cells. These data indicate that GABA released from β-cells functions as an autocrine inhibitor of insulin secretion in pancreatic islets and that the effect is principally due to direct suppression of exocytosis.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
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