| 10995774 |
Hoy M, Bokvist K, Xiao-Gang W, Hansen J, Juhl K, Berggren PO, Buschard K, Gromada J: Phentolamine inhibits exocytosis of glucagon by Gi2 protein-dependent activation of calcineurin in rat pancreatic alpha -cells. J Biol Chem. 2001 Jan 12;276(2):924-30.
Capacitance measurements were used to investigate the molecular mechanisms by which imidazoline compounds inhibit glucagon release in rat pancreatic alpha-cells. The imidazoline compound phentolamine reversibly decreased depolarization-evoked exocytosis > 80% without affecting the whole-cell Ca (2+) current. During intracellular application through the recording pipette, phentolamine produced a concentration-dependent decrease in the rate of exocytosis (IC (50) = 9.7 microm). Another imidazoline compound, RX871024, exhibited similar effects on exocytosis (IC (50) = 13 microm). These actions were dependent on activation of pertussis toxin-sensitive G (i2) proteins 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 alpha (2), I (1), and I (2) ligands. Phentolamine reduced glucagon release (IC (50) = 1.2 microm) 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 G (i2)-dependent activation of calcineurin in the pancreatic alpha-cell. The imidazoline binding site is likely to be localized intracellularly and probably closely associated with the secretory granules. |
34(0,1,1,4) |