Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS

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.

Ouabain Modulates the Functional Interaction Between Na,K-ATPase and NMDA Receptor

“…Allosteric receptor-receptor interaction, which is still an underexplored mechanism of receptor modulation [37], has been suggested to be an especially effective approach to control NMDA receptor function [38][39][40]. The functional readout from the interaction between two proteins is often modified by small molecules [41,42], and it is well established that ouabain binding to the potassium-binding state of the catalytic NKA subunit changes its conformation [43][44][45].…”

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…This is why the generation of bivalent DR ligands has been attempted by several groups ( Carli et al., 2018 ). The most common DR heterodimers/tetramers observed in vivo are D1/D2, D1/D3, D1/H3 and D2/A2A ( Borroto-Escuela and Fuxe, 2019 ). They all affect the MAPK response of these receptor systems, D1/D3 also modify recruitment of β-Arrestin-1 and heterodimer internalization.…”

Structural Complexity and Plasticity of Signaling Regulation at the Melanocortin-4 Receptor

“…Homo- [ 191 ] and hetero-oligomerization are widely accepted to be highly significant for GPCR functionalities [ 192 ]. The ability to form multimeric receptor assemblies affects physiological aspects [ 193 , 194 , 195 , 196 ] but is also associated with pathophysiological/pharmacological issues [ 197 , 198 , 199 , 200 , 201 ]. GPCR oligomerization can lead to modified ligand binding [ 187 , 202 , 203 , 204 ], G protein selectivity [ 205 ], signaling [ 206 , 207 , 208 ], or cell surface expression [ 209 , 210 ] and internalization [ 211 ].…”