Alpha-Adrenergic receptors mediate the actions of the catecholamines norepinephrine and epinephrine in a large number of tissues. In the liver, alpha-adrenergic receptors play a key role in regulating glucose metabolism and growth following hepatic injury. considerable evidence demonstrates that the hepatic responsiveness to alpha-adrenergic stimulation is regulated during early development, aging and hepatic regeneration; and that in part this regulation is accomplished through alterations in cellular alpha adrenergic receptor content. In this application, molecular biological and pharmacological techniques will be used to elucidate mechanisms involved in the tissue- and developmental-specific regulation of alpha-adrenergic receptor genes expression using the rat hepatocyte as the primary model.
The specific aims i n this application are: 1) establish the molecular basis for the tissue-specific expression of two primary alpha- adrenergic receptor genes transcripts, 3.3 kb and 2.7kb, by transcript mapping of genomic clones with cytoplasmic RNA isolated from liver (expresses both mRNAs) and heart (expresses only the 2.7 kb mRNA); 2) determine the functional significance of multiple alpha-adrenergic receptor gene transcripts by either expressing cDNAs in COS-7 cells and subsequently determining pharmacological and signal transduction properties of expressed receptors if sequence differences lie in the translated regions of the mRNAs, or alternatively if differences are in either 5'- or 3'-untranslated regions determine the effect of these differences on mRNA stability and translational efficiency; and 3) elucidate the molecular mechanisms involved in the regulation of hepatic alpha-adrenergic receptor gene expression during rate development by using DNase I hypersensitivity and DNA footprinting techniques to identify potential regulatory regions flanking the alpha-adrenergic receptor gene. The long term goal is to establish a complete understanding of the regulatory events involved in the control of alpha-adrenergic receptor gene expression. Accomplishing this involved in the control of alpha-adrenergic receptor gene expression. Accomplishing this goal should lead to a better understanding of disease states such as hypertension and certain metabolic disorders that are known to involve the alpha-adrenergic receptor.
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