Abstract
Exposure of primary cultures of embryonic rat striatal neurons to agents releasing nitric oxide (NO), including sin-1 molsidomine, S-nitroso-n-acetyl-penicillamine (SNAP), and S-nitrosoglutathione, resulted in an increase in the levels of expression of the immediate early genes c-fos and zif/268 in the cultured neurons. The membrane-permeable cGMP analogue, 8-bromo-cGMP, did not significantly affect c-fos and zif/268 mRNA levels, and the highly selective inhibitor of cGMP-dependent protein kinase, KT5823, was unable to inhibit the elevation in c-fos and zif/268 mRNA levels induced by SNAP. The induction of c-fos by the calcium ionophore A23187 was reduced by treatment with SNAP or 8-bromo-cGMP. Inhibitors of ADP-ribosyltransferases attenuated the stimulation of c-fos expression by SNAP. These results demonstrate for the first time that NO can induce immediate early gene expression in neurons, suggesting that NO may act as a mediator of neuronal plasticity via alterations in the expression of downstream genes. In addition, the results suggest that NO may exert these effects through a pathway that does not involve guanylate cyclase and cGMP-dependent protein kinase.
Highlights
A number of transcription factors have been identified that have the capacity to alter the rate of transcription of specific target genes in response to receptor-mediated signaling events at the cell membrane [1]
Ruthenium red, which has been proposed as an inhibitor of cADP-ribose-mediated mobilization of intracellular calcium, when applied to striatal cultures caused a massive induction of both c-fos and zif/268 mRNA levels (i.e. c-fos hybridization signal following vehicle treatment, Ϫ21.0 Ϯ 1.3 relative optical density units, n ϭ 14; following ruthenium red (30 M) Ϫ126.4 Ϯ 3.9 relative optical density units, n ϭ 7, p Ͻ 0.001)
We report here that exposure of rat striatal primary cultures to agents releasing nitric oxide resulted in dramatic increases in the levels of c-fos and zif/268 mRNAs
Summary
A number of transcription factors have been identified that have the capacity to alter the rate of transcription of specific target genes in response to receptor-mediated signaling events at the cell membrane [1]. I demonstrate here that NO is able to stimulate the expression of both c-fos and zif/268 in striatal neurons, and I provide evidence that the activation of guanylate cyclase and cGMP-dependent protein kinase does not play a major role in this effect.
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Published Version
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