Heteromers

A heteromer is a molecular complex formed by subunits that are different from one another. In contrast to homomers, which consist of identical subunits, heteromers combine distinct polypeptide chains to create a single functional unit. Heteromeric assemblies are common in protein networks, especially among receptors and ion channels, and they can assemble in various tissues and compartments inside the cell.

The formation of heteromers often changes the properties of the constituent subunits. Heteromerization can alter ligand binding, signaling pathway preference, channel conductance, trafficking, and regulatory interactions. In cell signaling, heteromeric G protein–coupled receptors can exhibit pharmacology and signaling biased relative to their parent receptors. Notable examples include dopamine D1–D2 receptor heteromers and adenosine A2A–D2 receptor heteromers, as well as heteromeric NMDA receptors composed of GluN1 with GluN2 subunits. Heteromeric nicotinic acetylcholine receptors (such as α4β2) and certain GABA-A receptor assemblies also illustrate this principle, with subunit composition shaping functional responses.

Detection and study of heteromers rely on biochemical and imaging approaches that reveal physical association and functional interaction. Methods include co-immunoprecipitation, cross-linking, fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), and proximity ligation assays. Challenges include distinguishing stable, physiologically relevant heteromers from transient or co-localized subunits and accounting for tissue- or condition-specific assembly. Understanding heteromerization enhances insights into signaling networks and can inform the development of more selective therapeutic agents.