Calmodulin-dependent regulation of inducible and neuronal nitric-oxide synthase

Shiow Ju Lee, James T. Stull

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


Neuronal and endothelial nitric-oxide synthases depend upon Ca2+/calmodulin for activation, whereas the activity of the inducible nitric-oxide synthase is Ca2+-independent, presumably due to tightly bound calmodulin. To study these different mechanisms, a series of chimeras derived from neuronal and inducible nitric-oxide synthases were analyzed. Chimeras containing only the oxygenase domain, calmodulin-binding region, or reductase domain of inducible nitric-oxide synthase did not confer significant Ca2+- independent activity. However, each chimera was more sensitive to Ca2+ than the neuronal isoform. The calmodulin-binding region of inducible nitric- oxide synthase with either its oxygenase or reductase domains resulted in significant, but not total, Ca2+-independent activity. Co- immunoprecipitation experiments showed no calmodulin associated with the former chimera in the absence of Ca2+. Trifluoperazine also inhibited this chimera in the absence of Ca2+. The combined interactions of calmodulin bound to inducible nitric-oxide synthase calmodulin-binding region with the oxygenase domain may be weaker than with the reductase domain. Thus, Ca2+- independent activity of inducible nitric-oxide synthase appears to result from the concerted interactions of calmodulin with both the oxygenase and reductase domains in addition to the canonical calmodulin-binding region. The neuronal isoform is not regulated by a unique autoinhibitory element in its reductase domain.

Original languageEnglish (US)
Pages (from-to)27430-27437
Number of pages8
JournalJournal of Biological Chemistry
Issue number42
StatePublished - Oct 16 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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