The changing world of G protein-coupled receptors: from monomers to dimers and receptor mosaics with allosteric receptor–receptor interactions

Abstract

Based on indications of direct physical interactions between neuropeptide and monoamine receptors in the early 1980s, the term receptor–receptor interactions was introduced and later on the term receptor heteromerization in the early 1990s. Allosteric mechanisms allow an integrative activity to emerge either intramolecularly in G protein-coupled receptor (GPCR) monomers or intermolecularly via receptor–receptor interactions in GPCR homodimers, heterodimers, and receptor mosaics. Stable heteromers of Class A receptors may be formed that involve strong high energy arginine–phosphate electrostatic interactions. These receptor–receptor interactions markedly increase the repertoire of GPCR recognition, signaling and trafficking in which the minimal signaling unit in the GPCR homomers appears to be one receptor and one G protein. GPCR homomers and GPCR assemblies are not isolated but also directly interact with other proteins to form horizontal molecular networks at the plasma membrane.

Keywords::

• Receptor heteromers
• receptor interface
• function of receptor heteromers
• horizontal molecular networks

Notes

¹Sir John Eccles in 1954, wrote “In conformity with Dale’s principle that the same chemical transmitter is released from all the synaptic terminals of a neurone(11). Some modern writers have understood the principle to state that neurons release one and only one transmitter at all of their synapses. Others, including Eccles himself in later publications, have taken it to mean that neurons release the same set of transmitters at all of their synapses.