Moonlighting Characteristics of G Protein-coupled Receptors: Focus on Receptor Heteromers and Relevance for Neurodegeneration

It is proposed that the moonlighting concept can be applied to G protein coupled receptors (GPCRs) as, obviously, they can carry out different types of functions. The same motifs in, for example, the third intracellular loop, can moonlight by switching between receptor–receptor interactions and interactions with signaling proteins such as G proteins or calmodulin. A ‘‘guide-and-clasp’’ manner of receptor–receptor interactions has been proposed where the ‘‘adhesive guides’’ may be the triplet homologies. As an example, the triplets AAR (or RAA) and AAE (or EAA) homologies in A2AR-D2R heteromers may guideand- clasp binding not only of the two protomers but also of calmodulin and Gi. A beautiful moonlighting phenomenon in the A2AR-D2R heteromer is that the positively charged D2R N-terminal third intracellular loop epitope (VLRRRRKRVN) may switch between bindings to the negatively charged A2AR epitope (SAQEpSQGNT), localized in the medium segment of the C terminus of the A2A receptor to several negative epitopes of calmodulin. Furthermore, overlapping motifs may favor moonlighting to Gi/o via inter alia electrostatic interaction between triplets AAR(in D2R third intracellular loop) and AAE (Gi/alpha1) (and/or their symmetric variants) contributing to guide-and-clasp D2R-Gi interactions Thus, moonlighting in GPCR heteromers can take place via allosteric receptor–receptor interactions and is also described in D1R-D2R, D2R-5- HT2R,and A1R-P2Y1 heteromers. Allosteric receptor–receptor interactions in GPCR-receptor tyrosine kinases (RTKs) heteromers and postulated ion channel receptor-RTK heteromers-like, for example, AMPA-NMDA-TrkB heteromers may lead to moonlighting of the participating GPCR and RTK protomers altering, for example, the pattern of the five major signaling pathways of the RTKs favoring MAPK and/or mTOR signaling with high relevance for neurodegenerative processes and depression induced atrophy of neurons. Moonlighting may also develop in the intracellular loops and C-terminal of the GPCRs as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptor.