Mechanisms of bradykinin-induced glucagon release in clonal alpha-cells In-R1-G9: involvement of Ca(2+)-dependent and -independent pathways.
The mechanisms by which bradykinin (BK) increases glucagon release were investigated. BK (0.1-10 microM) increased [Ca(2+)](i) and glucagon release in clonal alpha-cells In-R1-G9. BK-induced glucagon release was lower in the absence than in the presence of extracellular Ca(2+), but it still increased glucagon release while [Ca(2+)](i) was stringently deprived. Depletion of intracellular Ca(2+) store with thapsigargin abolished both the BK-induced Ca(2+) peak and sustained plateau. Microinjection of heparin abolished BK-induced Ca(2+) release. Pertussis toxin (PTX) did not block BK-induced [Ca(2+)](i) increase or glucagon release. U-73122 (8 microM), a phospholipase C (PLC) inhibitor, abolished BK-induced increases in [Ca(2+)](i), but only reduced BK-induced glucagon release by 40%. A phospholipase D (PLD) inhibitor zLYCK reduced BK-induced glucagon release by 60%. The combination of U-73122 and zLYCK abolished BK-induced glucagon release. Both SK&F 96365, a receptor-operated Ca(2+) channel (ROC) blocker and nimodipine, an L-type Ca(2+) channel blocker, reduced BK-induced [Ca(2+)](i) increase and glucagon release. These findings suggest that BK increase glucagon release through a PTX-insensitive G protein and both Ca(2+)-dependent and -independent pathways. The Ca(2+)-dependent pathway is attributable to PLC activation. PLC catalyzes IP(3) formation, inducing Ca(2+) release from the endoplasmic reticulum, which, in turn, triggers Ca(2+) influx via both ROCs and L-type channels. PLD activation may be involved in Ca(2+)-dependent and/or -independent pathway.
Yibchok-anun
S
S
Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA.
Cheng
H
H
Abu-Basha
E A
EA
Ding
J
J
Ioudina
M
M
Hsu
W H
WH
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000502:physiology; D005934:Glucagon / Q000378:metabolism*; D005935:Glucagonoma / Q000473:pathology; D006493:Heparin / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008647:Mesocricetus; D008845:Microinjections; D010190:Pancreatic Neoplasms / Q000473:pathology; D037342:Pertussis Toxin / Q000494:pharmacology; D010739:Phospholipase D / Q000502:physiology; D011760:Pyrrolidinones / Q000494:pharmacology; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000187:drug effects* / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D004963:Estrenes; D007093:Imidazoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011760:Pyrrolidinones; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D018160:Receptors, Cytoplasmic and Nuclear; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C074854:U 73343; D004533:Egtazic Acid; D019284:Thapsigargin; D006493:Heparin; D005934:Glucagon; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D010739:Phospholipase D; D019204:GTP-Binding Proteins; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D001920:Bradykinin; D002118:Calcium