Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development?

Abstract

The discovery of receptor-receptor interactions (RRI) has expanded our understanding of the role that G protein-coupled receptors (GPCRs) play in intercellular communication. The finding that GPCRs can operate as receptor complexes, and not only as monomers, suggests that several different incoming signals could already be integrated at the plasma membrane level via direct allosteric interactions between the protomers that form the complex. Most research in this field has focused on neuronal populations and has led to the identification of a large number of RRI. However, RRI have been seen to occur not only in neurons but also in astrocytes and, outside the central nervous system, in cells of the cardiovascular and endocrine systems and in cancer cells. Furthermore, RRI involving the formation of macromolecular complexes are not limited to GPCRs, being also observed in other families of receptors. Thus, RRI appear as a widespread phenomenon and oligomerization as a common mechanism for receptor function and regulation. The discovery of these macromolecular assemblies may well have a major impact on pharmacology. Indeed, the formation of receptor complexes significantly broadens the spectrum of mechanisms available to receptors for recognition and signaling, which may be implemented through modulation of the binding sites of the adjacent protomers and of their signal transduction features. In this context, the possible appearance of novel allosteric sites in the receptor complex structure may be of particular relevance. Thus, the existence of RRI offers the possibility of new therapeutic approaches, and novel pharmacological strategies for disease treatment have already been proposed. Several challenges, however, remain. These include the accurate characterization of the role that the receptor complexes identified so far play in pathological conditions and the development of ligands specific to given receptor complexes, in order to efficiently exploit the pharmacological properties of these complexes.

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

“…Neuronal influence on GFAP expression is due to alteration of extracellular ions and bioactive molecule levels as well as their activation of receptors and/or organic transporters on astrocyte membrane (Guidolin, Marcoli, Tortorella, Maura, & Agnati, ; Zhang et al, ). Increased neuronal activity can increase extracellular K + level which increases GFAP fiber formation, typically observed during seizures in hippocampus (Vizuete, Hennemann, Gonçalves, & de Oliveira, ).…”

“…The red lines/ arrows represent facilitatory pathways and the black lines/stops show inhibitory pathways. Abbreviations: AR, arginine residues; Ca 2+ /CAM, Ca 2 + /calmodulin; CDK5, cyclin-dependent kinase 5; CR, citrulline residues; CREB, cyclic AMP response element-binding protein; Ecrg4, esophageal cancer-related gene 4; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Glu, glutamate; gp130, glycoprotein 130; iNOS, inducible nitric oxide synthase; JAK2, Janus kinase-2; STAT3, signal transducer and activator of transcription 3; KDMs, histone lysine-specific demethylases; NMDAR, NMDA receptors; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; OSM, oncostatin M; PADs, peptidylarginine deiminases; PI3K/AKT, phosphatidylinositide 3-kinases; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PPARγ, peroxisome proliferator-activated receptor γ; TLR-4, Toll-like receptor 4; Trg, troglitazone receptors and/or organic transporters on astrocyte membrane (Guidolin, Marcoli, Tortorella, Maura, & Agnati, 2019;Zhang et al, 2019). Increased neuronal activity can increase extracellular K + level which increases GFAP fiber formation, typically observed during seizures in hippocampus (Vizuete, Hennemann, Gonçalves, & de Oliveira, 2017).…”

Are Synapse-Like Structures a Possible Way for Crosstalk of Cancer with Its Microenvironment?

“…This may supplement the immune checkpoint therapy, which is also targeted at disrupting synapses between the cancer cells and cells of the immune system. The formation of the clusters suggests that several different incoming signals could already be integrated at the plasma membrane level via direct allosteric interactions between the protomers that form the cluster [125]. It should lead to the emergence of new unpredictable features different from those expected from the properties of the interacting monomeric ligand-receptor pairs.…”

“…For example, the application of bivalent ligands composed of two functional pharmacophores linked by a spacer. This is considered in pharmacology as one of the most promising strategies for the treatment of homo or heterodimeric receptors (see, for example, [125,126]. Such kind of therapy may be a new way of tumor destruction.…”

Allosteric modulation of G protein‐coupled receptors by amiloride and its derivatives. Perspectives for drug discovery?

“…The interface for receptor dimerization often involves transmembrane domains 4 and 5 that are not part of the sodium ion binding site. In some cases, however, other domains such as TM6, which also flanks the sodium ion binding site, play a role …”