2. Pharmacology Unit, Faculty of Medicine, Department of Pathology and Experimental Therapeutics, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
3. Department of Molecular Medicine, University of Padova, Padua, Italy.
4. Department of Biomedical Sciences, University of Modena, Modena, Italy.
The allosteric receptor-receptor interactions over the interfaces in heteroreceptor complexes have been explored and their biochemical, pharmacological and functional integrative implications in the Central Nervous System (CNS) described. GPCR interacting proteins participate in these complexes mainly through modulation of receptor-receptor interactions. Methodologies to study heteroreceptor complexes in living cells (FRET and BRET-based techniques) and in brain tissue (in situ proximity ligation assay) are briefly summarized. The physiological and pathological relevance of the allosteric receptor-receptor interactions in heteroreceptor complexes is emphasized and novel strategies for treatment of mental and neurological disease are developed based on this new biological principle of integration. The molecular basis of learning and memory is proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses leading also to changes in the prejunctional receptor complexes to facilitate the pattern of transmitter release to be learned. 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 which can consolidate the heteroreceptor complexes into long-lived complexes with conserved allosteric receptor-receptor interactions.
Keywords: G protein coupled receptor, dimerization, in situ proximity ligation assay, allosteric receptorreceptor interactions, learning, memory, heteroreceptor complexes, mental and neurological disease