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Phentolamine Inhibits Exocytosis of Glucagon by Gi2Protein-dependent Activation of Calcineurin in Rat Pancreatic α-Cells*
- Source :
- Journal of Biological Chemistry; January 2001, Vol. 276 Issue: 2 p924-930, 7p
- Publication Year :
- 2001
-
Abstract
- Capacitance measurements were used to investigate the molecular mechanisms by which imidazoline compounds inhibit glucagon release in rat pancreatic α-cells. The imidazoline compound phentolamine reversibly decreased depolarization-evoked exocytosis >80% without affecting the whole-cell Ca2+current. During intracellular application through the recording pipette, phentolamine produced a concentration-dependent decrease in the rate of exocytosis (IC50= 9.7 μm). Another imidazoline compound, RX871024, exhibited similar effects on exocytosis (IC50= 13 μm). These actions were dependent on activation of pertussis toxin-sensitive Gi2proteins but were not associated with stimulation of ATP-sensitive K+channels or adenylate cyclase activity. The inhibitory effect of phentolamine on exocytosis resulted from activation of the protein phosphatase calcineurin and was abolished by cyclosporin A and deltamethrin. Exocytosis was not affected by intracellular application of specific α2, I1, and I2ligands. Phentolamine reduced glucagon release (IC50= 1.2 μm) from intact islets by 40%, an effect abolished by pertussis toxin, cyclosporin A, and deltamethrin. These data suggest that imidazoline compounds inhibit glucagon secretion via Gi2-dependent activation of calcineurin in the pancreatic α-cell. The imidazoline binding site is likely to be localized intracellularly and probably closely associated with the secretory granules.
Details
- Language :
- English
- ISSN :
- 00219258 and 1083351X
- Volume :
- 276
- Issue :
- 2
- Database :
- Supplemental Index
- Journal :
- Journal of Biological Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs7164473
- Full Text :
- https://doi.org/10.1074/jbc.M007562200