Nitric oxide inhibits ADP-ribosyl cyclase through a cGMP-independent pathway in airway smooth muscle.
There is evidence for a role of cyclic ADP-ribose (cADPR) in intracellular Ca2+ regulation in smooth muscle. cADPR is synthesized and degraded by ADP-ribosyl cyclase and cADPR hydrolase, respectively, by a bifunctional protein, CD38. Nitric oxide (NO) inhibits intracellular Ca2+ mobilization in airway smooth muscle. The present study was designed to determine whether this inhibition is due to regulation of ADP-ribosyl cyclase and/or cADPR hydrolase activity. Sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine, NO donors, produced a concentration-dependent decrease in ADP-ribosyl cyclase, but not cADPR hydrolase, activity. The NO scavenger carboxy-PTIO prevented and reversed, and reduced glutathione prevented, the inhibition of ADP-ribosyl cyclase by SNP, suggesting S-nitrosylation by NO as a mechanism. N-ethylmaleimide, which covalently modifies protein sulfhydryl groups, making them incapable of nitrosylation, produced a marked inhibition of ADP-ribosyl cyclase, but not cADPR hydrolase, activity. SNP and N-ethylmaleimide significantly inhibited the ADP-ribosyl cyclase activity in recombinant human CD38 without affecting the cADPR hydrolase activity. These results provide a novel mechanism for differential regulation of CD38 by NO through a cGMP-independent pathway involving S-nitrosylation of thiols.
White
Thomas A
TA
Department of Veterinary PathoBiology, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108, USA.
Walseth
Timothy F
TF
Kannan
Mathur S
MS
D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors*; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D005033:Ethylmaleimide / Q000494:pharmacology; D066298:In Vitro Techniques; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013552:Swine; D014132:Trachea / Q000187:drug effects / Q000502:physiology*
D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D036541:ADP-ribosyl Cyclase; D006152:Cyclic GMP; D005033:Ethylmaleimide