B-ADRENERGIC RECEPTOR ACTIVATION AND EXPRESSION

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.