The beta-adrenergic receptors (Beat-AR) regulate a wide variety of physiological processes through their interactions with catecholamines. Two subtypes of beta-adrenergic receptors have been distinguished by differential potency of several adrenergic receptor agonists in promoting physiological effects in the heart, ling, and nervous sysstem. The beta-adrenergic receptor subjtypes are functionally similar, but are differentially expressed. In many species, including man, cardiac contraction is controlled primarily through beta1-adrenergic receptors, while bronchial relation is moderated principally by beta-adrenergic receptors. Abnormalities in the expression of these receptors have been implicated in playing roles in cardiovascular diseases, such as cardiac hypertrophy and hypertesnion, in bronchial asthma, and in hyperthyroidism. While much is known about the physiological responses of beeta- adrenergic receptors to catecholamines, our understanding of the molecular mechanisms that mediate receptor subtype activation and expression is limited. Our laboratory has cloned the beta1- and beta2-adrenergic receptor genes and has expessed the beta-rectptor by gene transfer into the beta-adrenergic receptor-deficient mouse l cell system. The overall goals of this research program are to analyze the molecular structure, orgainization, and expression of the beta1- and beta2-adrenergic receptor genes differential expression of the beta-adrenergic receptor subtypes.
The specific aims are: 1) to characterize the expression of the beta2-adrenergic receptor in transfectant mouse L cells and to examine beta2-AR transcriptional activity during receptor desensitization and recycling and upon corticosteroid hormone stimulation; 2) to utilize receptor antisense mRNA and gene transfer technology to inhibit beta2- adrenergic receptor mutants using a novel selection and replica filter screening approach; 4) to utilize site-directed mutagenesis of the beta2-AR gene to examine effects of glycosylation on receptor processing to the cell surface; 5) to sequence and express the rat beta1-adrenergic receptor gene and to analyze its expression in embryonic heart cells; and 6) to analyze interdependent modes of regulation between the two beta-adrenergic receptor subtypes.
