Intramembrane receptor-receptor interactions: A novel principle in molecular medicine

K. Fuxe, M. Canals, M. Torvinen, D. Marcellino, A. Terasmaa, S. Genedani, G. Leo, D. Guidolin, Z. Diaz-Cabiale, A. Rivera, L. Lundstrom, U. Langel, J. Narvaez, S. Tanganelli, C. Lluis, S. Ferré, A. Woods, R. Franco, L. F. Agnati

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental 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 receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (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 processes. 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 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible 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 medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.

Original languageEnglish (US)
Pages (from-to)49-75
Number of pages27
JournalJournal of Neural Transmission
Issue number1
StatePublished - Jan 2007
Externally publishedYes


  • A2A receptors
  • Basal ganglia
  • D2-like receptors
  • Learning and memory
  • Metabotropic glutamate receptor 5
  • Neuropeptide receptors
  • Novel treatment strategies in neuropsychopharmacology
  • Receptor heteromers
  • Receptor mosaics

ASJC Scopus subject areas

  • General Neuroscience


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