Structure, Function, and Regulation of the Three β‐Adrenergic Receptors

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Abstract
Three β‐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 exta‐ 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 β1/β2 antagonists (the well known β blockers) act as agonists on β3. The subtype is resistant to short‐term desensitization mediated by phosphorylation through PKA or βARK, in stark contrast to the β1 or β2 subtypes. Various compounds (dexamethasone, butyrate, insulin) up regulate β1 or β1 subtypes while down‐regulating β3 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.