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J. Biol. Chem., Vol. 276, Issue 2, 924-930, January 12, 2001

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Phentolamine Inhibits Exocytosis of Glucagon by G_i2 Protein-dependent Activation of Calcineurin in Rat Pancreatic -Cells^*

Marianne Høy, Krister Bokvist, Weng Xiao-Gang, John Hansen, Kirstine Juhl, Per-Olof Berggren, Karsten Buschard^§, and Jesper Gromada^¶

From the Laboratory of Islet Cell Physiology, Novo Nordisk A/S, Novo Alle, DK-2880 Bagsvaerd, ^§ Bartholin Instituttet, Kommunehospitalet, Øster Farimagsgade 5, DK-1353 Copenhagen, Denmark and  The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Karolinske Hospital L1:02, S-171 76 Stockholm, Sweden

Capacitance measurements were used to investigate the molecular mechanisms by which imidazoline compounds inhibit glucagon release in rat pancreatic -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 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 ₂, I₁, and I₂ ligands. 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 G_i2-dependent activation of calcineurin in the pancreatic -cell. The imidazoline binding site is likely to be localized intracellularly and probably closely associated with the secretory granules.

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