H]spiperone in the absence of sodium ions raclopride exerted noncompetitive effects, decreasing the number of sites labeled by the radioligand. These data are interpreted in terms of a model where the receptor exists as a dimer, and in the absence of sodium ions, raclopride exerts negative cooperativity across the dimer both for its own binding and the binding of spiperone. A model of the receptor has been produced that provides a good description of the experimental phenomena described here.The G-protein-coupled receptors (GPCRs) 1 constitute a large family of proteins responsible for the transduction of a wide range of signals (e.g. hormones, neurotransmitters, odorants, light, etc.) via G-proteins (1). GPCRs possess a common structural motif of seven ␣-helical membrane-spanning domains, and it is often assumed that the functional unit (i.e. the ligand binding and G-protein interaction domains) of the GPCR is wholly contained in a single polypeptide. Indeed, most models of GPCR function assume a monomeric receptor interacting with the G-protein (see, for example, Ref. 2). Several lines of evidence, however, suggest that the some GPCRs may exist in dimeric or oligomeric forms.Immunoblotting has in several cases revealed species corresponding not only to the predicted molecular weight of the receptor but also to multiples of the molecular weight. Bands corresponding to approximately twice the predicted molecular weight of the receptor have been interpreted as homodimers for several receptors including D 2 dopamine (3, 4), D 3 dopamine (5),  2 -adrenergic (6), substance P (7), opiate (8) and M 1 and M 2 muscarinic acetylcholine receptors (9). Co-immunoprecipitation has also been used to demonstrate homodimer formation for the  2 -adrenergic receptor (6), opiate receptor (8), and somatostatin SSTR5 receptor (10). In some cases, formation of heterodimers of GPCRs has been reported with differences in the pharmacological properties of the receptors in the heterodimer (e.g. GABA B receptor isoforms (11-13), ␦ and opiate receptors (14), dopamine, and somatostatin receptors (10)).Further evidence for interaction of GPCRs was provided by Maggio et al. (15), who created two chimeric receptors ␣ 2 /M 3 and M 3 /␣ 2 , in which the C-terminal regions (transmembrane domains VI and VII) were exchanged between the ␣ 2C adrenergic and M 3 muscarinic receptors. Expression of either chimera alone did not result in any detectable binding of typical radiolabeled muscarinic or adrenergic ligands. However, cotransfection of COS7 cells with both chimeras resulted in the appearance of binding activity corresponding to both native receptors. This has lead to the proposal that some GPCRs might form domain-swapped dimers (16). Evidence for GPCR interaction in cells has been obtained by expressing GPCRs fused to different chromophores. Transfer of energy between the chromophores has been shown for the  2 -adrenergic receptor (17) and somatostatin SSTR5 receptor (10) and provides good evidence for the close proximity of the two molecules...