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Neuronal death may be modulated by the activity of signal transduction systems that influence the toxicity of NO or its metabolic products such as cGMP. The enzyme responsible for the production of NO, nitric oxide synthase (NOS), is phosphorylated by protein kinase C (PKC), the cAMP\u2010dependent protein kinase (PKA), and the calcium\/calmodulin\u2010dependent protein kinase II (CaM\u2010II). We examined in primary cultured hippocampal neurons whether the protein kinases PKC, PKA, CaM\u2010II, and cGMP\u2010dependent protein kinase modified the toxic effects of anoxia and NO. Down\u2010regulation of PKC activity with PMA (1\u03bcM) increased hippocampal neuronal survival during anoxia and NO exposure from approximately 22% to 88%. Inhibitors of PKC activity 9H\u20107, H\u20108, sphingosine, and staurosporine also were neuroprotective. Down\u2010regulation of PKC activity increased survival during anoxia even in the presence of the NOS inhibitor, N<jats:sup>\u03c9<\/jats:sup>\u2010methyl\u2010L\u2010arginine. Thus, although down\u2010regulation of PKC activity may increase neuronal survival by decreasing NOS activity, it also is likely that PKC contributes to ischemic neuronal death by mechanisms that are independent of NOS. Inhibition of the cGMP\u2010dependent protein kinase activity, but not the activity of the CaM\u2010II also was neuroprotective during NO administration. In contrast to the protective effects of inhibition of PKC and the cGMP\u2010dependent protein kinase, activation rather than inhibition of PKA increased hippocampal neuronal survival during NO exposure. These results indicate that neuronal survival during anoxia and NO exposure is linked to the modulation of PKC, PKA, and cGMP\u2010dependent protein kinase activity but is not dependent on the CaM\u2010II pathway. Understanding the involvement of PKC, PKA, and the cGMP\u2010dependent protein kinase in modulating the effect of neuronal death during ischemia and NO toxicity may help in directing future therapeutic modalities for cerebrovascular disease. \u00a9 1993 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.490360109","type":"journal-article","created":{"date-parts":[[2005,1,1]],"date-time":"2005-01-01T01:51:53Z","timestamp":1104544313000},"page":"77-87","source":"Crossref","is-referenced-by-count":62,"title":["Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia"],"prefix":"10.1002","volume":"36","author":[{"given":"K.","family":"Maiese","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. 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