Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease

Abstract

The introduction of allosteric receptor–receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor–receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. 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. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-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 (DA) and adenosine signals involve A2AR-D2R 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 and A2AR-D2R-Sigma1R heteroreceptor complex holds high promise as a new way to treat cocaine use disorders. Neuromodulation of neuronal networks in schizophrenia via DA, adenosine, glutamate, 5-HT and neurotensin peptides and oxytocin, involving A2AR-D2R, D2R-NMDAR, A2AR-D2R-mGluR5, D2R-5-HT2A and D2R-oxytocinR heteroreceptor complexes opens up a new world of D2R protomer targets in the listed heterocomplexes for treatment of positive, negative and cognitive symptoms of schizophrenia.

D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

“…In line with the recent identification of GPCR heteromers as functional units and potential drug targets (58,59), the present dissection of the D1-mGlu5 heteromer biochemical fingerprint could prompt a development of screening tools and ligands for therapeutic research. Compared with antagonizing ubiquitous D1 or mGlu5 receptors, disrupting the D1-mGlu5 heteromer is predicted to offer a better risk-benefit profile for the treatment and prevention of LID.…”

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control

“…Genes found to be involved in neuronal development and misregulated by STAG1 and STAG2 degradation were tested in neural stem cells under control (Ctrl), STAG1 (shSTAG1), STAG2 (shSTAG2), and SMC1A (shSMC1A) siRNA knockdown to test whether they depend specifically on STAG1 or STAG2 or on the presence of the cohesin complex in general. The tested genes are: CDK6, associated with microcephaly (Faheem et al 2015); AXL, intellectual disability (Burstyn-Cohen 2017); IL6ST, neural protection and development (März et al 1997); ADAM19, neurogenesis (Alfandari and Taneyhill 2018); GAL, neuro-regulatory peptide-encoding gene (Borroto-Escuela et al 2017). Mean of n = 3; t-test P-values are indicated.…”

Adenosine and Its Receptors as Potential Drug Targets in Amyotrophic Lateral Sclerosis

“…64 The ability of A 2A R to control dopaminergic inputs in the basal ganglia is widely known, as well as its implications for Parkinsons' disease, drug addiction, and even schizophrenia. 58,59,65 Another relevant role of adenosine A 2A R is their ability to gate the action of neurotrophins, this action being well documented at the level of the forebrain, with implications for synaptic plasticity 66,67 as well as most probably for neuroprotection and neuroregeneration. 68 It is important to highlight, however, that A 2A R may act as a double-edged sword, being extensively documented for their ability to exacerbate excitotoxicity by promoting glutamate release and inhibiting glutamate uptake.…”