HORMONE CONTROL OF PREPROTACHYKININ-A GENE EXPRESSION

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Cell-to-cell communication is often subserved by peptides in neural and peripheral tissues. Regulation of peptide synthesis is an important step controlling this communication. This application examines processes regulating synthesis of two related peptides, substance P (SP) and substance K (SK), using molecular biological techniques. SP and SK are encoded by the same preprotachykinin-A (PPT-A) gene and are selectively distributed in neural and endocrine tissues, including the anterior pituitary. Experiments will examine hormonal and neural regulation of SP and SK concentrations and expression of the PPT-A gene in anterior pituitary and several discrete neural sites. These experiments are divided into four areas: 1) SP and SK content and PPT-A mRNA abundance are regulated by thyroid hormone and sex steroid hormones in the anterior pituitary. Proposed experiments will determine if PPT-A mRNA abundance is related to transcription of the PPT-A gene or PPT-A mRNA degradation. 2) SP concentration and PPT-A mRNA abundance in caudate putamen is regulated by dopamine and by opiates. In other neural regions, including hypothalamus, amygdala and preoptic regions, SP concentrations change during the estrous cycle and after gonadectomy. Experiments will determine if hormones regulate PPT-A gene expression in neural tissues. 3) The primary PPT-A RNA transcript undergoes a series of alternate splicings to yield three mature PPT-A mRNAs. Tissue and subcellular localization of PPT-A mRNAs be examined to determine if there are tissue and/or hormone-induced differences in their distribution. 4) Experiments will determine if cis-acting elements associated with the PPT-A gene confer hormonal regulation to its expression. These studies will elucidate mechanisms by which expression of the PPT-A gene is regulated in endocrine and neural tissues and enhance understanding of how production of peptides can be regulated by hormones at the molecular level.