GPCR Heteroreceptor Complexes as Modulators of Brain Networks and as Targets for Treatment of Mental and Neurological Diseases

Dear Colleagues,

GPCR-containing heteroreceptor complexes involving, e.g., ionotropic and RTK receptors in the brain give a new dimension to brain integrative processes and to neuropsychopharmacology. The molecular assessment of heteroreceptor complexes was made by co-expressing them in cellular models involving HEK293T cells and primary cultures from brain regions using quantitative confocal microscopy imaging techniques, appropriate in situ proximity ligation assays, biophysical FRET/BRET experiments including Co-IP, and mutation studies. The molecular processes of learning and memory may be based on the reorganization of the homo- and heteroreceptor complexes in the postsynaptic and extrasynaptic membrane of synapses, including also increased formation of adaptor proteins participating in these receptor complexes. Allosteric receptor–receptor interactions in such heteroreceptor complexes were evaluated with biochemical binding techniques. These interactions play a major role in increasing receptor plasticity and produce enhancement in the diversity of GPCR function with development of biased recognition and signaling and highly specific receptor responses in each receptor heteromer. Each individual receptor heteromer may also be selectively targeted by heterobivalent compounds and interface-interacting peptides, making it possible to explore their function in health and disease. Brain disease can develop as a result of dysfunction of distinct heteroreceptor complexes and their balance with other homo–heteroreceptor complexes. In the case of several types of 5-HT receptor-containing heteroreceptor complexes, in which galanin and oxytocin receptors can participate, there are indications that disturbances within them can contribute to depression, e.g., through errors in the serotonin modulation of the limbic networks of emotion. Regarding treatment of cocaine use disorder, the A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes are of particular interest in view of their potential critical role in modulating the ventral striatopallidal GABA anti-reward neurons of the nucleus accumbens, opening up the possibility for improved treatment of cocaine addiction. Mu–Delta opioid heteroreceptor complexes instead appear to have a critical role in morphine addiction. There is also support for the hypothesis that multiple adenosine A2AR-D2R like complexes have a role in schizophrenia and in Parkinson’s disease. A new world of heteroreceptor complex targets is opening up in neuropsychopharmacology for treatment of brain disease. Original and review papers should cover an update of the field of heteroreceptor complexes in neuronal and glial networks of the brain and their integrative role under physiological and pathological conditions, including mental disease and neurological disease.

You are invited to participate in this Special Issue in Cells. We hope you will find this research field of interest.

Prof. Kjell Fuxe
Dr. Dasiel O. Borroto-Escuela
Guest Editors

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• receptor heteromer
• heteroreceptor complexes
• allosteric receptor–receptor interactions
• GPCR
• neuromodulation
• brain
• brain disease
• neuropsychopharmacology
• depression
• substance use disorder
• schizophrenia
• Parkinson’s disease