Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylate Cyclase Toxin
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Animals
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Calcineurin / metabolism*
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Cells, Cultured
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Clorgyline / pharmacology
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Cyclosporine / pharmacology
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Cystamine / analogs & derivatives*
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Cystamine / pharmacology
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Diazoxide / pharmacology
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Exocytosis / drug effects*
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GTP-Binding Protein alpha Subunit, Gi2
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GTP-Binding Protein alpha Subunits, Gi-Go / antagonists & inhibitors
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GTP-Binding Protein alpha Subunits, Gi-Go / genetics
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
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Glucagon / metabolism*
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Imidazoles / pharmacology
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Indoles / pharmacology
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Islets of Langerhans / drug effects
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Islets of Langerhans / physiology*
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Nitriles
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Oligodeoxyribonucleotides, Antisense / pharmacology*
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Pertussis Toxin
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Phentolamine / pharmacology*
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Potassium Channels / drug effects
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Potassium Channels / physiology*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Pyrethrins / pharmacology
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Rats
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Rats, Inbred Lew
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Virulence Factors, Bordetella / pharmacology
Substances
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2-(2-imidazolin-2-yl)-1-phenyl-1H-indole
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Adenylate Cyclase Toxin
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Imidazoles
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Indoles
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Nitriles
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Oligodeoxyribonucleotides, Antisense
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Potassium Channels
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Proto-Oncogene Proteins
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Pyrethrins
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Virulence Factors, Bordetella
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decamethrin
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benextramine
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Cyclosporine
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Glucagon
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Pertussis Toxin
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Calcineurin
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GTP-Binding Protein alpha Subunit, Gi2
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GTP-Binding Protein alpha Subunits, Gi-Go
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Gnai2 protein, rat
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Clorgyline
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Diazoxide
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Cystamine
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Phentolamine