Basic Pharmacological and Structural Evidence for Class A G-Protein-Coupled Receptor Heteromerization (original) (raw)
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The Journal of biological chemistry, 2003
The histamine H1 receptor and the ␣ 1b -adrenoreceptor are G protein-coupled receptors that elevate intracellular [Ca 2؉ ] via activation of G q /G 11 . Assessed by coimmunoprecipitation and time-resolved fluorescence resonance energy transfer they both exist as homodimers. The addition of the G protein G 11 ␣ to the C terminus of these receptors did not prevent dimerization. Agonists produced a large stimulation of guanosine
The Journal of endocrinology, 2008
Dimerization or oligomerization of G-protein-coupled receptors (GPCRs) is a novel concept, which may lead to the reevaluation of the actions of pharmacological ligands, hormones, neurotransmitters, and other mediators acting on GPCRs. Although a large number of data obtained using different biophysical, biochemical and structural methods, and functional approaches argue for dimerization or oligomerization of these receptors, several publications criticized the applied methods and challenged the concept. The aim of this paper is to review the data that support the concept of receptor oligomerization, and the most important arguments against it. We conclude that it will require major methodical improvements to obtain decisive proof, whether GPCRs exist in their native membrane environments as homo- or heterodimeric or oligomeric complexes, in which receptor monomers have stable direct interactions. However, overwhelming amounts of data suggest that many GPCRs exhibit functional proper...
Molecular Pharmacology, 2001
The availability of a high-resolution structure of rhodopsin now allows us to reconsider research attempts to understand structure-function relationships in other G protein-coupled receptors (GPCRs). A comparison of the rhodopsin structure with the results of previous sequence analysis and molecular modeling that incorporated experimental results demonstrates a high degree of success for these methods in predicting the helix ends and protein-protein interface of GPCRs. Moreover, the amino acid residues inferred to form the surface of the bindingsite crevice based on our application of the substituted-cysteine accessibility method in the dopamine D 2 receptor are in remarkable agreement with the rhodopsin structure, with the notable exception of some residues in the fourth transmembrane segment. Based on our analysis of the data reviewed, we propose that the overall structures of rhodopsin and of amine receptors are very similar, although we also identified localized regions where the structure of these receptors may diverge. We
The G protein-coupled receptor rhodopsin in the native membrane
FEBS Letters, 2004
The higher-order structure of G protein-coupled receptors (GPCRs) in membranes may involve dimerization and formation of even larger oligomeric complexes. Here, we have investigated the organization of the prototypical GPCR rhodopsin in its native membrane by electron and atomic force microscopy (AFM). Disc membranes from mice were isolated and observed by AFM at room temperature. In all experimental conditions, rhodopsin forms structural dimers organized in paracrystalline arrays. A semi-empirical molecular model for the rhodopsin paracrystal is presented validating our previously reported results. Finally, we compare our model with other currently available models describing the supramolecular structure of GPCRs in the membrane.
Class A G-Protein-Coupled Receptor (GPCR) Dimers and Bivalent Ligands
Journal of Medicinal Chemistry, 2013
G protein-coupled receptors (GPCRs) represent the largest family of membrane proteins involved in cellular signal transduction and are activated by various different ligand types including photons, peptides, proteins but also small molecules like biogenic amines. Therefore, GPCRs are involved in diverse physiological processes and provide valuable drug targets for numerous diseases. Emerging body of evidence suggests that GPCRs exist either as monomers or cross-react forming dimers and higher-ordered oligomers. In this perspective we will review on current biochemical and biophysical techniques to visualize GPCR dimerization, functional consequences of homo-and heterodimers as well as approaches of medicinal chemists to target these receptor complexes with homo-and heterobivalent ligands.