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 A(2A) R-D2 R heteromers may guide-and-clasp binding not only of the two protomers but also of calmodulin and G(i) . A beautiful moonlighting phenomenon in the A(2A) R-D2 R heteromer is that the positively charged D2 R N-terminal third intracellular loop epitope (VLRRRRKRVN) may switch between bindings to the negatively charged A(2A) R 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 G(i/o) via inter alia electrostatic interaction between triplets AAR(in D2 R third intracellular loop) and AAE (G(i/alpha1) ) (and/or their symmetric variants) contributing to guide-and-clasp D2 R-G(i) interactions Thus, moonlighting in GPCR heteromers can take place via allosteric receptor-receptor interactions and is also described in D1 R-D2 R, D2 R-5-HT2 R,and A1 R-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.