Moonlighting Proteins and Protein–Protein Interactions as Neurotherapeutic Targets in the G Protein-Coupled Receptor Field

Abstract

There is serious interest in understanding the dynamics of the receptor-receptor and receptor-protein interactions in space and time and their integration in GPCR heteroreceptor complexes of the CNS. Moonlighting proteins are special multifunctional proteins because they perform multiple autonomous, often unrelated, functions without partitioning into different protein domains. Moonlighting through receptor oligomerization can be operationally defined as an allosteric receptor-receptor interaction, which leads to novel functions of at least one receptor protomer. GPCR-mediated signaling is a more complicated process than previously described as every GPCR and GPCR heteroreceptor complex requires a set of G protein interacting proteins, which interacts with the receptor in an orchestrated spatio-temporal fashion. GPCR heteroreceptor complexes with allosteric receptor-receptor interactions operating through the receptor interface have become major integrative centers at the molecular level and their receptor protomers act as moonlighting proteins. The GPCR heteroreceptor complexes in the CNS have become exciting new targets for neurotherapeutics in Parkinson's disease, schizophrenia, drug addiction, and anxiety and depression opening a new field in neuropsychopharmacology.

Receptor-receptor interactions in heteroreceptor complexes: a new principle in biology. Focus on their role in learning and memory

“…This may involve alterations of receptor protomer recognition (affinity and receptor density) and of the strength of G protein coupling leading to modulatory effects on the receptor protomer signaling cascades and on ion channel activity in the plasma membrane like G protein-coupled inwardly-rectifying potassium channels. A major change brought about by the allosteric receptor-receptor interaction is the change of protomer function through a change in its G protein selectivity from e.g., Gi to Gq or favouring receptor protomer signaling over b-arrestin [100][101][102]. The GPCRs behave as moon-lighting proteins [16] and biased signaling of the GPCR protomers develop [103][104][105].…”

Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes

“…Homotropic cooperativity is not possible, but allosteric interactions can occur, causing a change in the recognition/decoding processes of the monomers (see upper panel of Figure 3). Thus, it has been shown that depending on which partner is costimulated, the affinity of the D2 receptor for dopamine is either reduced (as in the adenosine A2A-D2 hetero-oligomer; Fuxe et al, 2003Fuxe et al, , 2014 or enhanced (as in the somatostatin SST5-D2 heterooligomer; Rocheville et al, 2000;Agnati et al, 2005b).…”

Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5

“…These heteroreceptor complexes are mainly located in the dorsal and ventral striato-pallidal GABA neurons predominantly found in a perisynaptic position outside the postsynaptic membrane of the glutamate synapse operating via volume transmission ( Figure 4) [72,73]. The formation of heteroreceptor complexes may also lead to changes in the allosteric receptor binding sites including their pharmacology [74].…”