Receptor-receptor interactions in heteroreceptor complexes: a new principle in biology. Focus on their role in learning and memory

Abstract

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.

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…Recently identified direct interactions with RTK (BorrotoEscuela et al, 2012;Di Liberto et al, 2017), indeed, open the possibility that GPCR complexes could modulate structural changes at the level of dendrites and dendritic spines. Furthermore, the reorganization of GPCR complexes in the postjunctional membrane of synapses and their possible stabilization by the interaction with specific adapter proteins could represent a molecular mechanism for learning and memory Fuxe et al, 2014b;Borroto-Escuela et al, 2015).…”

“…Furthermore, the system exhibited a limited number of equilibrium configurations or 'attractors', leading to the hypothesis that such a set of configurations could be interpreted as a form of information storage (engram) at the level of synapses and intercellular connections (Agnati et al, 1982Guidolin et al, 2007). Thus, the suitable reorganization of receptor complexes in the postsynaptic membrane has been recently proposed as the molecular basis of learning and memory (Fuxe et al, 2014b;Borroto-Escuela et al, 2015).…”

“…Hsp-40, GRP78, and PDI) that aid the folding and maturation of receptors (see Fuxe et al, 2014b). Without the assistance of these chaperones, GPCR will be directed either to degradation (e.g.…”

“…Thus, receptor complexes are in the center of multiple receptor-protein and protein-protein interactions that can influence their assemblage and stoichiometry (see Fuxe et al, 2014b).…”

The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural–glial networks

“…The relevance of this transmission for learning and short-and long-term memory will be discussed [24]. A few examples will be given on how certain 5-HT1A and Nmethyl-D-aspartate (NMDA) heteroreceptor complexes can play a role in depression and schizophrenia, respectively, and be targets for novel antidepressant and atypical antipsychotic drugs [25][26][27].…”