DEVELOPMENTAL REGULATION OF THE B1 ADRENERGIC RECEPTOR GENE

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Beta adrenergic receptors (betaAR) are members of the G-protein coupled receptor family which includes receptors for a variety of neurotransmitters and hormones. Because of their critical role in physiological functions such as myocardial contractility, betaAR responsiveness is tightly controlled. It is well established that betaAR are regulated by corticosteroids and thyroid hormones. Most of these studies were done in tissue culture or in adult animal models and nearly all were done on the beta2 adrenergic receptor. In contrast, there are few or no studies on beta1AR receptors or in developing fetal animals. We have shown that neither glucocorticoids nor thyroid hormones increase beta1AR in fetal animals whereas there is an increase in animals treated after birth. Thus, the regulation of beta1AR by glucocorticoids and thyroid hormones in the fetus is distinct from that of adults. This switch in beta1AR responsiveness may represent a unique form of developmentally regulated transcription. We hypothesize that the unique transcriptional regulation of beta1AR gene expression in developing animals compared to adults is due to the presence of specific transcription factors which interfere with the hormone-receptor and gene interaction. To study this mechanism, we have cloned the ovine beta1AR gene and 5' flanking region. Progressive deletions of the promoter have been made and are being used for identification of glucocorticoid and thyroid hormone response elements (GRE and TRE). We have identified a region within the 5' flanking region which confers glucocorticoid responsiveness as well as repression of basal transcription. The current proposal is designed (1) to determine the role of these elements in fetal maturation, (2) to identify and clone the transcription factor(s) responsible for this unique form of transcriptional regulation. These will be the first reported studies to map the promoter of the beta1AR gene and will be of importance in understanding the pathophysiology of cardiovascular diseases at all developmental stages.