A PEPTIDE DERIVED FROM A BETA(2)-ADRENERGIC RECEPTOR TRANSMEMBRANE DOMAIN INHIBITS BOTH RECEPTOR DIMERIZATION AND ACTIVATION

One of the assumptions of the mobile receptor hypothesis as it relates to G protein-coupled receptors is that the stoichiometry of receptor, G protein, and effector is 1:1:1 (Bourne, H. R,, Sanders, D, A, and M cCormick, F, (1990) Nature 348, 125-132), Many studies on the cooperat ivity of agonist binding are incompatible with this notion and have su ggested that both G proteins and their associated receptors can be oli gomeric. However, a clear physical demonstration that G protein-couple d receptors can indeed interact as dimers and that such interactions m ay have functional consequences was lacking, Here, using differential epitope tagging we demonstrate that beta(2)-adrenergic receptors do fo rm SDS-resistant homodimers and that transmembrane domain VI of the re ceptor may represent part of an interface for receptor dimerization, T he functional importance of dimerization is supported by the observati on that a peptide derived from this domain that inhibits dimerization also inhibits beta-adrenergic agonist-promoted stimulation of adenylyl cyclase activity. Moreover, agonist stimulation was found to stabiliz e the dimeric state of the receptor, while inverse agonists favored th e monomeric species, which suggests that interconversion between monom eric and dimeric forms may be important for biological activity.