Inducible nitric-oxide synthase attenuates vasopressin-dependent Ca2+ signaling in rat hepatocytes.
Increases in both Ca(2+) and nitric oxide levels are vital for a variety of cellular processes; however, the interaction between these two crucial messengers is not fully understood. Here, we demonstrate that expression of inducible nitric-oxide synthase in hepatocytes, in response to inflammatory mediators, dramatically attenuates Ca(2+) signaling by the inositol 1,4,5-trisphosphate-forming hormone, vasopressin. The inhibitory effects of induction were reversed by nitric oxide inhibitors and mimicked by prolonged cyclic GMP elevation. Induction was without effect on Ca(2+) signals in response to AlF(4)(-) or inositol 1,4,5-trisphosphate, indicating that phospholipase C activation and release of Ca(2+) from inositol 1,4,5-trisphosphate-sensitive Ca(2+) stores were not targets for nitric oxide inhibition. Vasopressin receptor levels, however, were dramatically reduced in induced cultures. Our data provide a possible mechanism for hepatocyte dysfunction during chronic inflammation.
Patel
Sandip
S
Department of Physiology, University College London, Gower Street, London WC1E 6BT, United Kingdom. patel.s@ucl.ac.uk
Gaspers
Lawrence D
LD
Boucherie
Sylviane
S
Memin
Elisabeth
E
Stellato
Kerri Anne
KA
Guillon
Gilles
G
Combettes
Laurent
L
Thomas
Andrew P
AP
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000032:analysis; D010738:Type C Phospholipases / Q000502:physiology; D014667:Vasopressins / Q000494:pharmacology*
D017483:Receptors, Vasopressin; D014667:Vasopressins; D009569:Nitric Oxide; D015544:Inositol 1,4,5-Trisphosphate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D006152:Cyclic GMP; D002118:Calcium