Structure, function, and regulation of the three beta-adrenergic receptors.

Abstract

Three beta-adrenergic receptor subtypes are now known to be functionally expressed in mammals. All three belong to the R7G family of receptors coupled to G-proteins, and characterized by an extracellular glycosylated N-terminal and an intracellular C-terminal region and seven transmembrane domains, linked by three extra- and three intracellular loops. The catecholamine ligand binding domain, studied using affinity-labeling and site-directed mutagenesis, is a pocket lined by residues belonging to the transmembrane domains. The region responsible for the interaction with the Gs protein which, when activated, stimulates adenylyl cyclase, is composed of residues belonging to the parts most proximal to the membrane of intracellular loop i3 and the C-terminal region. The pharmacology of the three subtypes is quite distinct: in fact most of the potent beta 1/beta 2 antagonists (the well known beta blockers) act as agonists on beta 3. The subtype is resistant to short-term desensitization mediated by phosphorylation through PKA or beta ARK, in stark contrast to the beta 1 or beta 2 subtypes. Various compounds (dexamethasone, butyrate, insulin) upregulate beta 1 or beta 2 subtypes while down-regulating beta 3 whose expression strictly correlates with differentiation of 3T3-F442A fibroblasts into adipocytes, thus confirming that the expression of the three subtypes may each be regulated independently to exert a specific physiologic role in different tissues or at different stages of development.