NMDA AND NITRIC-OXIDE ACT THROUGH THE CGMP SIGNAL-TRANSDUCTION PATHWAY TO REPRESS HYPOTHALAMIC GONADOTROPIN-RELEASING-HORMONE GENE-EXPRESSION

The key roles of the excitatory neurotransmitter glutamate and its sec ond messengers, nitric oxide (NO) and cGMP, in long-term potentiation and neural plasticity are well documented. However, complex functions such as memory are likely to require long term changes in synaptic eff icacy which require gene expression and protein synthesis, Here we dem onstrate that the glutamate receptor agonist, N-methyl-D-aspartic acid (NMDA), nitric oxide (NO) and cGMP each repress expression of the gon adotropin-releasing hormone (GnRH) gene in the hypothalamic cell line, GT1, This repression is dependent upon signals from NMDA receptors ac tivating NO synthase to synthesize NO, In turn NO induces guanylyl cyc lase to synthesize cGMP, activating cGMP-dependent protein kinase, Rep ression requires elevation of calcium because it only occurs in the pr esence of a calcium ionophore or with release of intracellular calcium , Repression also requires protein synthesis, Activation of this pathw ay specifically represses expression of a reporter gene containing the regulatory region of the GnRH gene in transfected GT1 cells, indicati ng that repression occurs at the transcriptional level. Furthermore th e target for transcriptional repression is a 300 bp neuron-specific en hancer found 1.5 kb upstream of the GnRH gene which is sufficient to c onfer repression to a heterologous promoter. Thus the NMDA/NO/cGMP neu rotransmitter signal transduction pathway controls not only synaptic f unction but also neuron-specific gene expression.