Abstract
G protein-coupled receptors (GPCRs) not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place, modulating the functions of the participating GPCR protomers. GPCRs can also form heteroreceptor complexes with ionotropic receptors and receptor tyrosine kinases modulating their function. Furthermore, adaptor proteins interact with receptor protomers and modulate their interactions. The state of the art is that the allosteric receptor-receptor interactions are reciprocal, highly dynamic and substantially alter the signaling, trafficking, recognition and pharmacology of the participating protomers. The pattern of changes appears to be unique for each heteromer and can favor antagonistic or facilitatory interactions or switch the G protein coupling from e.g., Gi/o to Gq or to beta-arrestin signaling. It lends a new dimension to molecular integration in the nervous system. Future direction should be aimed at determining the receptor interface involving building models of selected heterodimers. This will make design of interface-interfering peptides that specifically disrupt the heterodimer possible. This will help to determine the functional role of the allosteric receptor-receptor interactions as well as the integration of signals at the plasma membrane by the heteroreceptor complexes, vs. integration of the intracellular signaling pathways. Integration of signals also at the plasma membrane seems crucial in view of the hypothesis that learning and memory at a molecular level takes place by reorganization of homo and heteroreceptor complexes in the postsynaptic membrane. Homo and heteroreceptor complexes are in balance with each other, and their disbalance is linked to disease. Targeting heteroreceptor complexes represents a novel strategy for the treatment of brain disorders.
Highlights
A couple of years earlier GABA(A) receptor activation had been found, by our group, to reduce the affinity of the high affinity D2R agonist binding sites in membrane preparations from the dorsal striatum (Pérez de la Mora et al, 1997). These results indicated the existence of allosteric receptor-receptor interactions in D2R-GABA(A)R complexes
In 2007, we introduced the hypothesis of the existence of G protein-coupled receptor (GPCR)-receptor tyrosine kinase (RTK) heteroreceptor complexes based on their potential direct receptor-receptor interactions (Fuxe et al, 2007)
When we introduced the concept of allosteric intramembrane receptor-receptor interactions in heteroreceptor complexes in the 1980s, there was little interest in this concept (Fuxe et al, 1983)
Summary
Amylin is known to inhibit both insulin release and food intake This impressive work underlines the dynamic regulation of the CGRP and calcitonin receptors by plasma membrane proteins and its impact on trafficking, recognition and signaling of these GCPRs. As discussed in the article of Hay et al (2016), it seems likely that RAMPs can interact with a large number of class B GPCRs and certain class A and C GPCRs leading to allosteric changes in receptor recognition, signaling and trafficking of the participating GPCRs. Adaptor/chaperone proteins like Sigma1R that bind to the receptor protomers can substantially modulate the receptorreceptor interactions (Pinton et al, 2015b; Beggiato et al, 2017; Borroto-Escuela et al, 2017b). Likely that allosteric A2AR-D2R interactions (Figure 2) can participate in such events since they were shown to inhibit D2R Gi/o mediated signaling and increase D2R mediated beta-arrestin signaling through recruitment of beta-arrestin to the intracellular surface of the D2R (Borroto-Escuela et al, 2011b; Figure 1)
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