BETA1 ADRENERGIC RECEPTOR ACTIVATION & EXPRESSION

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The -adrenergic receptors ( -ARs) are important modulators in the sympathetic control of various metabolic processes in the central and peripheral nervous system, including the heart. There is a limited understanding of the molecular mechanisms that regulate -AR subtype activation, expression, and desensitization in the normal and failing heart. The 1-adrenergic receptor ( 1-AR) subtype is localized predominantly in the heart and is believed to be the principal modulator of the rate and force of cardiac contraction. My laboratory has cloned, sequenced, and expressed the rat and rhesus macaque 1-adrenergic receptor genes. We have defined the 1-AR transcriptional start sites, promoter elements, and polyadenylation sites used for expression in the C6 glioma cell line, and have identified potential enhancer and repressor regions that influence 1-AR expression. In addition, we have defined the primary 1-AR promoter in cardiac myocytic cells, and have determined that 1-AR transcription in the heart occurs predominantly from downstream start sites. Furthermore, we have demonstrated that the inducible cAMP early repressor (ICER) is induced in C6 cells by 1-AR agonists, and that ICER interacts with the 1-AR promoter to down-regulate 1-AR mRNA transcription, with resultant diminution of cell surface receptor. Additional research is now centered on identifying genomic elements and trans-activators of 1-AR transcription, with the use of 1-AR luciferase-reporter recombinants, transfection assays, DNA mobility shift and DNase footprinting assays. The overall focus of this project is to precisely identify functional regulatory elements and factors involved in the regulation of the 1-adrenergic receptor gene, and to analyze the transcriptional activation of the 1-adrenergic receptor subtype during receptor desensitization and hormonal stimulation. Research will initially utilize rodent tissues, prior to the use of nonhuman primate tissues, in the identification of 1-AR transactivators.