title: Long lasting inhibition of adenylyl cyclase selectively mediated by inositol 1,4,5-trisphosphate-evoked calcium release.
abstract: In A7r5 smooth muscle cells, vasopressin stimulates release of Ca2+ from intracellular stores and Ca2+ entry, and it inhibits adenylyl cyclase (AC) activity. Inhibition of AC is prevented by inhibition of phospholipase C or when the increase in cytosolic [Ca2+] is prevented by the Ca2+ buffer, BAPTA. It is unaffected by pertussis toxin, inhibition of protein kinase C, or L-type Ca2+ channels or by removal of extracellular Ca2+. The independence of extracellular Ca2+ occurs despite inhibition of AC by vasopressin persisting for at least 15 min, whereas the cytosolic [Ca2+] returns to its basal level within 1-2 min in Ca2+-free medium. Although capacitative Ca2+ entry (CCE), activated by emptying stores with thapsigargin, inhibits AC, Ca2+ entry via CCE or L-type Ca2+ channels activated by vasopressin is ineffective. Temporally separating vasopressin-evoked Ca2+ release from the assessment of AC activity revealed that the transient Ca2+ signal resulting from Ca2+ mobilization causes a long lasting inhibition of AC. By contrast, inhibition of AC by thapsigargin-evoked CCE reverses rapidly after removal of extracellular Ca2+. Inhibition of AC by vasopressin is prevented by inhibition of Ca2+-calmodulin-dependent protein kinase II. We conclude that persistent inhibition of AC (probably AC-3) by vasopressin is mediated by inositol trisphosphate-evoked Ca2+ release causing activation of Ca2+-calmodulin-dependent protein kinase II. Our results establish that an important interaction between two ubiquitous signaling pathways is tuned selectively to Ca2+ release via inositol trisphosphate receptors and that the interaction transduces a transient Ca2+ signal into a long lasting inhibition of AC.
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, United Kingdom.
authors.forename: Jeanette L
authors.initials: JL
authors.lastname: Dyer
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Liu
authors.forename: Irene Pino
authors.initials: IP
authors.lastname: de la Huerga
authors.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D009130:Muscle, Smooth / Q000201:enzymology; D037342:Pertussis Toxin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D020746:Calcium Channels, L-Type; D001127:Arginine Vasopressin; D004533:Egtazic Acid; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium