J Neural Transm (2007) 114: 49–75 DOI 10.1007/s00702-006-0589-0 Printed in The Netherlands Intramembrane receptor–receptor interactions: a novel principle in molecular medicine  K. Fuxe 1 , M. Canals 1;3 , M. Torvinen 1 , D. Marcellino 3 , A. Terasmaa 1 , S. Genedani 2 , G. Leo 2 , D. Guidolin 2;9 , Z. Diaz-Cabiale 4 , A. Rivera 5 , L. Lundstrom 6 , U. Langel 6 , J. Narvaez 4 , S. Tanganelli 7 , C. Lluis 3 , S. Ferre ´ 8 , A. Woods 8 , R. Franco 3 , L. F. Agnati 2 1 Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institutet, Stockholm, Sweden 2 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, and IRCCS of Venezia, Italy 3 Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain 4 Department of Physiology, Faculty of Medicine, University of Malaga, Malaga, Spain 5 Department of Cell Biology, School of Science, University of Malaga, Malaga, Spain 6 Department of Neurochemistry, University of Stockholm, Stockholm, Sweden 7 Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy 8 National Institute on Drug Abuse, IRP, NIH, Department of Health and Human Services, Baltimore, MD, USA 9 Department of Anatomy and Human Physiology, University of Padova, Padova, Italy Received: January 1, 2006 = Accepted: October 4, 2006 = Published online: October 27, 2006 # Springer-Verlag 2006 Summary In 1980=81 Agnati and Fuxe introduced the concept of intra- membrane receptor–receptor interactions and presented the first experimen- tal observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor–receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor–receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor–receptor interactions namely the presence of regulated cooperativity via receptor–receptor interactions in re- ceptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor–receptor in- teractions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor com- position (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor–receptor interactions are outlined and long- lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval pro- cesses. Intramembrane receptor–receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson’s disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 ago- nists) and depression (galanin receptor antagonists). The A2A=D2, A2A=D3 and A2A=mGluR5 heteromers and heteromeric complexes with their pos- sible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A=D4 heteromers. Finally, the impact of intramembrane receptor–receptor interactions in molecular med- icine is discussed outside the brain with focus on the endocrine, the cardio- vascular and the immune systems. Keywords: A2A receptors, D2-like receptors, metabotropic glutamate receptor 5, neuropeptide receptors, receptor heteromers, receptor mosaics, basal ganglia, novel treatment strategies in neuropsychopharmacology, learning and memory Introduction The dawn of the concept In 1980=81 Agnati and Fuxe introduced the concept of in- tramembrane receptor–receptor interactions and presented the first experimental observations for their existence in  Dedicated to Prof. Rolf Luft, Department of Endocrinology, Karolinska Institutet, Stockholm, Sweden for His outstanding research and teaching that inspired an entire generation of scientists worldwide in the field of molecular medicine. Correspondence: Kjell Fuxe, Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institutet, 17177 Stockholm, Sweden e-mail: Kjell.Fuxe@ki.se