Regulation of neuronal nitric oxide and cyclic GMP formation by Ca2+.
Nitric oxide (NO) acts as a messenger molecule in the CNS by activating soluble guanylyl cyclase. Rat brain synaptosomal NO synthase was stimulated by Ca2+ in a concentration-dependent manner with half-maximal effects observed at 0.3 microM and 0.2 microM when its activity was assayed as formation of NO and L-citrulline, respectively. Cyclic GMP formation was apparently inhibited, however, at Ca2+ concentrations required for the activation of NO synthase, indicating a down-regulation of the signal in NO-producing cells. Purified synaptosomal guanylyl cyclase was not inhibited directly by Ca2+, and the effect was not mediated by a protein binding to guanylyl cyclase at low or high Ca2+ concentrations. In cytosolic fractions, the breakdown of cyclic GMP, but not that of cyclic AMP, was highly stimulated by Ca2+, and 3-isobutyl-1-methylxanthine did not block this reaction effectively. The effects of Ca2+ on cyclic GMP hydrolysis and on apparent guanylyl cyclase activities were abolished almost completely in the presence of the calmodulin antagonist calmidazolium, whose effect was attenuated by added calmodulin. Thus, a Ca2+/calmodulin-dependent cyclic GMP phosphodiesterase is highly active in synaptic areas of the brain and may prevent elevations of intracellular cyclic GMP levels in activated, NO-producing neurons.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002147:Calmodulin / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D008297:Male; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D051381:Rats; D013574:Synaptosomes / Q000201:enzymology / Q000378:metabolism
D002147:Calmodulin; D009569:Nitric Oxide; D010744:Phosphoric Monoester Hydrolases; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine