The activation of neuronal nitric-oxide synthase by various divalent cations.
Nitric-oxide synthase (NOS; EC 1.14.13.39) catalyzes the oxidation of L-arginine to nitric oxide (NO(.)) and L-citrulline via the intermediate N(omega)-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 Ca(2+)/calmodulin binding region. To activate NOS I, Ca(2+) 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 Pb(2+), 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 Pb(2+) and Sr(2+) can activate NOS I to a level similar to that found for Ca(2+). Finally, there is a synergy between Pb(2+) and Ca(2+) resulting in maximal activation of NOS I using minimal concentrations of both metal ions.
Department of Chemistry, School of Pharmacy, University of Maryland Baltimore County, 725 W Lombard Street, Baltimore, MD 21201, USA.
John
J
Weaver
Supatra
S
Porasuphatana
Pei
P
Tsai
Guan-Liang
GL
Cao
Theodore A
TA
Budzichowski
Linda J
LJ
Roman
Gerald M
GM
Rosen
D000818:Animals; D001120:Arginine / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology*; D002254:Carbonates / Q000494:pharmacology*; D002413:Cations, Divalent / Q000494:pharmacology*; D002956:Citrulline / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D007854:Lead / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D013324:Strontium / Q000494:pharmacology
D002254:Carbonates; D002413:Cations, Divalent; D009419:Nerve Tissue Proteins; D002956:Citrulline; D007854:Lead; D009569:Nitric Oxide; C043262:lead carbonate; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C025700:strontium chloride; D002118:Calcium; D013324:Strontium