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Receptor heteromers constitute a new area of research that is reshaping our thinking about biochemistry, cell biology, pharmacology and drug discovery. In this commentary, we recommend clear definitions that should facilitate both information exchange and research on this growing class of transmembrane signal transduction units and their complex properties. We also consider research questions underlying the proposed nomenclature, with recommendations for receptor heteromer identification in native tissues and their use as targets for drug development.

The physiological meaning of the coexpression of adenosine A2A receptors and group I metabotropic glutamate receptors in ␥-aminobutyric acid (GABA)ergic striatal neurons is intriguing. Here we provide in vitro and in vivo evidence for a synergism between adenosine and glutamate based on subtype 5 metabotropic glutamate (mGluR5) and adenosine A2A ( A denosine is a neuromodulator that plays a very important role in basal ganglia function (1). Its actions are mediated by specific G protein-coupled receptors, which are currently classified in A1, A2A, A2B, and A3 subtypes (2). Compared with the other adenosine receptor subtypes, A2A receptors (A2ARs) are concentrated in the striatum (1, 3), where they are expressed mostly by ␥-aminobutyric acid (GABA)ergic striatopallidal neurons (4). The recent ultrastructural analysis performed by Hettinger et al. (5) has demonstrated that, in the rat, A2ARs are localized mostly postsynaptically in the dendrites and dendritic spines of striatal GABAergic neurons. A2AR immunoreactivity was observed primarily at glutamatergic (asymmetric) synapses (5). Therefore, it was suggested that A2AR plays a prominent role in modulating glutamatergic input to striatal GABAergic neurons (5).Glutamate acts on both ionotropic and metabotropic G protein-coupled receptors (mGluRs). Molecular and pharmacological characterization studies have currently divided the mGluR family into three groups (I-III) (6). Group I mGluR includes mGluR1 and mGluR5, with the latter being highly expressed in the striatum, particularly in the striatal GABAergic efferent neurons (7). In the striatopallidal complex in primates, mGluR5 showed a localization very similar to that described for A2AR in rats. Thus, mGluR5 immunoreactivity was commonly found postsynaptically and perisynaptically to asymmetric synapses (8). These studies provide a morphological basis for the possible existence of functional interactions between striatal A2AR and mGluR5. In fact, in recent in vivo microdialysis experiments we found functional evidence for the possible existence of synergistic A2AR͞mGlluR5 interactions modulating the function of the GABAergic striatopallidal neurons originating in the nucleus accumbens (9). In the present study we provide evidence for the existence of A2AR͞mGluR5 heteromeric complexes in membrane preparations from human embryonic kidney (HEK)-293 cells transiently cotransfected with both receptors and from rat striatum. Furthermore, the same kind of functional A2AR͞mGluR5 synergistic interaction (induction of the immediate-early gene c-fos) could be demonstrated both in cotransfected cells and the rat striatum. These results suggest that A2AR͞mGluR5 synergistic interactions can have important implications for striatal neuronal function and dysfunction.

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