Abstract
Nitric-oxide synthase (NOS; EC 1.14.13.39) catalyzes the oxidation ofl-arginine to nitric oxide (NO⋅) andl-citrulline via the intermediateNω-hydroxy-l-arginine. Of the three distinct isoforms of NOS that have been characterized, the constitutive neuronal NOS (NOS I) generates NO⋅associated with long-term potentiation (LTP) and early brain development. All of the NOS isoforms contain an N-terminal oxidase and a C-terminal reductase domain connected by a Ca2+/calmodulin binding region. To activate NOS I, Ca2+ has to bind to calmodulin, allowing electron transport through both domains. Calcium ions are tightly regulated in cells. However, a number of other metal ions that bind and activate calmodulin may also activate NOS I. One such metal ion may be Pb2+, which is associated with neurobehavioral and psychological alterations, including the inhibition of LTP. The effect of various divalent cations on NOS I activity was tested, and the results presented herein demonstrate that Pb2+ and Sr2+ can activate NOS I to a level similar to that found for Ca2+. Finally, there is a synergy between Pb2+ and Ca2+ resulting in maximal activation of NOS I using minimal concentrations of both metal ions.
Footnotes
-
This research was supported in part by grants from the National Institutes of Health (RR-12257 to G.M.R., T32-ES07263 to P.T., R25-GM55036 to J.W., and GM52419 to L.J.R.).
-
DOI: 10.1124/jpet.102.035337
- Abbreviations:
- NO⋅
- nitric oxide
- NOS
- nitric-oxide synthase
- LTP
- long-term potentiation
- BMPO
- 5-tert-butoxycarbonyl-5-methyl-1-pyrrolineN-oxide
- H4B
- (6R)-5,6,7,8-tetrahydro-l-biopterin dihydrochloride (tetrahydrobiopterin)
- Received February 26, 2002.
- Accepted April 25, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|