oa Editorial [Hot Topic: Relevance of Integration at the Membrane Level of Receptor-Receptor Interactions in Neurodegenerative Diseases and Drug Addiction (Guest Editor: Sergio Tanganelli)]

A receptor-receptor interaction occur “when the binding of a ligand to the orthosteric or allosteric sites of one receptor causes, via direct allosteric interactions, a change in the ligand recognition, decoding, and trafficking processes of another receptor”. Thus, it demands the formation of receptor heterodimers or higher order heteromers, to form the so called “receptor mosaics”. In view of the likely existence of disease and tissue specific heteromers, novel strategies for drug treatment based on targeting the heterodimers and receptor mosaics, have recently been introduced. Such drugs will have reduced side effects by targeting the heteromers versus the monomers and homomers. It is well known that allostery is a mode of long distance communication between distal sites in proteins. The allosteric mechanisms make possible an integrative activity to emerge either intramolecularly in G protein-coupled receptor (GPCR) monomers or intermolecularly via receptor-receptor interactions in GPCR homodimers, heterodimers, and receptor mosaics. In the receptor heteromers, the allosteric communication between the two receptors takes place via the receptor interface, which therefore plays a key role in mediating the receptor- receptor interaction. The allosteric mechanisms in receptor heteromers make possible a marked rise of the repertoire of GPCR recognition and signaling. This is achieved through the modulation of the orthosteric and allosteric binding sites of the adjacent protomer and of its G protein activation, its G protein selectivity, its signaling cascades with among others switching from G protein to β-arrestin signaling and through appearance of novel allosteric sites that may alter for instance G protein coupling and selectivity. GPCRs can also form complexes with ion-channel receptors. The main focus in this mini hot topic issue is on the relevance of receptor complexes, such as A2A-D2 heteromers and NMDA-NTS1 receptor interactions, for an improved understanding of the etiopathogenesis of Parkinson's disease, schizophrenia and cocaine addiction as well as for the development of new pharmacological strategies. Furthermore, new hypothetical strategies for other pharmacological interventions besides the classical approaches, are herein suggested.