{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T00:53:43Z","timestamp":1792976023359,"version":"4.5.0"},"reference-count":88,"publisher":"National Academy of Sciences","issue":"20","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,9,25]]},"abstract":"<jats:p>\n                    The heme oxygenase (HO) and nitric oxide (NO) synthase (NOS)\n systems display notable similarities as well as differences. HO and NOS\n are both oxidative enzymes using NADPH as an electron donor. The\n constitutive forms of the enzyme are differentially activated, with\n calcium entry stimulating NOS by binding to calmodulin,\n whereas calcium entry activates protein kinase C to phosphorylate and\n activate HO2. Although both NO and carbon monoxide (CO) stimulate\n soluble guanylyl cyclase to form cGMP, NO also S-nitrosylates selected\n protein targets. Both involve constitutive and inducible biosynthetic\n enzymes. However, functions of the inducible forms are virtual\n opposites. Macrophage-inducible NOS generates NO to kill other cells,\n whereas HO1 generates bilirubin to exert antioxidant cytoprotective\n effects and also provides cytoprotection by facilitating iron extrusion\n from cells. The neuronal form of HO, HO2, is also cytoprotective.\n Normally, neural NO in the brain seems to exert some sort of behavioral\n inhibition. However, excess release of NO in response to glutamate's\n                    <jats:italic>N<\/jats:italic>\n                    -methyl-\n                    <jats:sc>d<\/jats:sc>\n                    -aspartate receptor activation\n leads to stroke damage. On the other hand, massive neuronal firing\n during a stroke presumably activates HO2, leading to neuroprotective\n actions of bilirubin. Loss of this neuroprotection after HO inhibition\n by mutant forms of amyloid precursor protein may mediate neurotoxicity\n in Familial Alzheimer's Disease. NO and CO both appear to be\n neurotransmitters in the brain and peripheral autonomic nervous system.\n They also are physiologic endothelial-derived relaxing factors for\n blood vessels. In the gastrointestinal pathway, NO and CO appear to\n function as coneurotransmitters, both stimulating soluble guanylyl\n cyclase to cause smooth muscle relaxation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.191351298","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:10Z","timestamp":1027679650000},"page":"10996-11002","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":254,"title":["Neural roles for heme oxygenase: Contrasts to nitric oxide synthase"],"prefix":"10.1073","volume":"98","author":[{"given":"David E.","family":"Bara\u00f1ano","sequence":"first","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, and Psychiatry and Behavioral\r Sciences, The Johns Hopkins University School of Medicine, Baltimore,\r MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solomon 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