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Department of Pharmacology

Dyer, JL, Liu, Y, De La Huerga, IP, Taylor, CW

In A7r5 smooth muscle cells, vasopressin stimulates release of Ca 2+ 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 [Ca 2+] is prevented by the Ca2+ buffer, BAPTA. It is unaffected by pertussis toxin, inhibition of protein kinase C, or L-type Ca 2+ 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 [Ca 2+] 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 Ca 2+ signal into a long lasting inhibition of AC. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

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Published date: 
11 March 2005
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Publication type: 
Journal articles
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Journal of Biological Chemistry
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