セカンドメッセンジャーを介する神経遺伝子発現制御の薬理学

抄録

Second messenger systems regulate transcription initiation of immediate-early genes (IEGs) through phosphorylation of transcriptional factors and repressors. Tissue-specific late response genes (LRGs) are induced dependently on protein synthesis slowly after IEGs, but the mechanisms of regulation of LRGs are still unknown. In this review, the mechanisms of transcriptional regulation of IEGs are summarized and possible drug action sites are discussed. As to the neuropeptide Y (NPY) gene, a typical neuronal LRG, the approach was introduced to elucidate the transcriptional regulations of the NPY gene induced by membrane depolarization and NGF-induced neuronal differentiation. The second messenger systems were Ca/calmodulin dependent protein kinases (CaM) and NGF-induced MAP kinases, respectively. The unique CaM- and NGF-responsive elements and DNA-binding factors were identified. The NDF1 protein bound to NGF-RE were cloned and characterized. NDF1 seems to a novel transcriptional factor that regulates neurotrophin-induced transcription of LRGs. Thus identification of novel regulatory factors is required to elucidate mechanisms of gene expression including transcriptional initiation, and pharmacological studies are also necessary to discover the novel drug action sites in the gene expression system.