Understanding the role of heteroreceptor complexes in the central nervous system.

This special issue is based on a mini-symposium in the area of neurosciences with the title "Understanding the role of heteroreceptor complexes in the central nervous system" held at the Nobel Forum, Karolinska Institutet on December 17th, 2012, organized by Kjell Fuxe, Dasiel O. Borroto-Escuela and Luigi F. Agnati. It consists of seven mini-reviews in the field receptor heteromers. The early work on negative cooperativity and neuropeptide-monoamine receptor-receptor interactions in the central nervous system gave the first indications of the existence of homomers and heteromers of G-protein coupled receptors (GPCR), respectively, and the GPCR field began to expand from monomers into dimers and receptor mosaics (higher-order dimers). It was underlined that the existence of receptor heteromers with allosteric receptor-receptor interactions increases the diversity and bias of GPCR recognition and signalling. The molecular phenomenon of allosteric receptor-receptor interactions is proposed to give a better understanding of brain function through molecular integration of signals. An alteration in specific receptor-receptor interactions is in fact considered to play a role in pathogenic mechanisms leading to several diseases, inter alia Parkinson's disease, hypertension, schizophrenia, addiction and depression. It is a new principle in molecular medicine. Therefore, pharmacological targeting of receptor-receptor interactions in heteromers will become an important area for developing more selective drugs with reduced side-effects including heterobivalent compounds and optimal types of combined treatments. In other words , it will lead to novel strategies for treatment, and finally novel drugs for treatment of disease. The first mini-review by Dr. Tena-Campus and colleagues introduces the field of GPCR oligomerization as emerging signalling units with new opportunities for drug design and discusses the technologies involved for detection of receptor heteromers. Then the issue moves into examples of receptor-receptor interactions in the DA and neuropeptide field. Dr. Van Craenenbroeck and colleagues presents an article on the role of dimerization in the biogenesis of DA D4 receptors and thus in their maturation. Dr. Zaida Diaz-Cabiale and colleagues describe the existence of galanin receptor-neuropeptide Y receptor interactions in the brain including galanin receptor-neuropeptide Y Y1 interactions in the brain stem. Indications are obtained that the receptor target for galanin fragment 1-15 is instead a GalR1-GalR2 heteromer. Then the special issue enters into the role of receptor-receptor interactions in putative striatal GPCR heteromers in Parkinson's disease and schizophrenia. Dr. Beggiato and colleagues discuss the role of antagonistic adenosine A2A-D2 receptorreceptor interactions in the striato-pallidal GABA neurons and their relevance for treatment of Parkinson's disease. They give the rationale for the introduction of A2A receptor antagonists in clinical trials in this disease based on these antagonistic receptor- receptor interactions which become even more strongly developed in animal models of Parkinson's disease. Dr. Luca Ferraro and colleagues instead discuss in detail the antagonistic Neurotensin NTS1-dopamine D2 receptor-receptor interactions in putative receptor heteromers in the dorsal and ventral striatum. Their involvement in striato-pallidal GABA and mesocorticolimbic DA communication is discussed with focus on their relevance for Parkinson's disease, schizophrenia and their treatments. Dr. Di Liberto and colleagues deal with the role of receptor-receptor interactions in brain trophism and plasticity with focus on interactions between G protein-coupled receptor-Receptor Tyrosine Kinase, specially the cholinergic and fibroblast growth factor receptor 1 (FGFR1). mAChR-FGFR1 interactions are indicated leading to transactivation of FGFR1 with potential relevance for cognition. Luigi Agnati and colleagues in the last paper of this special issue suggest a unified perspective for integrative brain actions through " neurosemeiotics" and " free energy minimization". Especially the Bio-semeiotics concept of "adaptor" may involve the receptor-receptor interactions in heteroreceptor complexes. Through such "adaptors" a code may be produced that give meaning to the sensory stimuli reaching the cortical regions of the brain . We hope the readers will find the articles in this special issue of interest and may give some inspiration to enter this exciting field of receptor research in the CNS which opens up a novel understanding of the molecular events that may lead to neurological and mental diseases and offer novel strategies for their treatments. The editors are grateful to the authors for their fine contributions to this special issue.