Building a new conceptual framework for receptor heteromers

Abstract

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.

Figure 1

Examples of heteromeric receptors, receptor heteromers and receptors with associated modifying proteins. (a) The glutamate NMDA receptor as an example of a heteromeric ionotropic receptor. The NMDA receptor is a tetrameric complex formed by NR1 and NR2 subunits (only two subunits are shown) that bind glycine and glutamate, respectively. (b) The GABA_B receptor heteromeric receptor as an example of a heteromeric GPCR. GABA_B1 and GABA_B2 subunits establish coiled-coil interactions between their C termini. (c) The A_2A-D₂ receptor heteromer. The C terminus of the adenosine A_2A receptor binds to the long third intracellular loop of the dopamine D₂ receptor; whether this and other receptor heteromers are dimeric or higher order oligomeric species remains to be established. (d) The D₁-NMDA receptor heteromer, as an example of a receptor heteromer with a heteromeric receptor as one of the receptor units; the C termini of the NR1 and NR2 (NR2A) subunits bind to different epitopes of the C terminus of the dopamine D₁ receptor. (e) The MT₁-GPR50 receptor, formed by the association of the melatonin MT₁ receptor and the orphan 7TM protein GPR50. TM domains are probably involved in the oligomerization, while the long C terminus of GPR50 is mostly involved in the modulation of MT₁ receptor function. (f) The amylin (AMY) receptor, formed by the oligomerization of the calcitonin (CT) receptor and the single transmembrane protein RAMP; the two proteins bind through their N-terminal domains. In b–f, two subunits are shown for schematic purposes, without ruling out multimerization.