On the role of the balance of G protein-coupled receptor (GPCR) homo and heteroreceptor complexes and their integration of signals in neurons and astroglia. Relevance for brain disorders

Abstract

There exists substantial evidence for the existence of G protein-coupled receptor (GPCR) homo and heteroreceptor complexes with allosteric receptor-receptor interactions in the Central Nervous System (CNS). The formation of homo-and heteroreceptor complexes in a synaptic or extrasynaptic area of the plasma membrane is governed by several factors and especially by the density of the participating receptor protomers. Another factor is the affinity of one receptor protomer for another protomer, which is related to the number of hot spots that can develop in the receptor interface. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. In depression neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT, galanin peptides and neuropeptide Y involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR2-NPYY1R, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine and adenosine signals involve A2AR-D2R, A2AR-D2R-mGluR5 and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and ventral striatum. The excitatory modulation by A2AR agonists of the ventral striato-pallidal GABA anti-reward system via targeting the A2AR-D2R, A2AR-D2R-mGluR5 and A2AR-D2R-Sigma1R heteroreceptor complex holds high promise as a new way to treat cocaine use disorders.