GPCR heteromers and their allosteric receptor-receptor interactions

K. Fuxe, D. O. Borroto-Escuela, D. Marcellino, W. Romero-Fernández, M. Frankowska, D. Guidolin, M. Filip, L. Ferraro, A. S. Woods, A. Tarakanov, F. Ciruela, L. F. Agnati, S. Tanganelli

Research output: Contribution to journalArticlepeer-review


The concept of intramembrane receptor-receptor interactions and evidence for their existences were introduced in the beginning of the 1980's, suggesting the existence of receptor heterodimerization. The discovery of GPCR heteromers and the receptor mosaic (higher order oligomers, more than two) has been related to the parallel development and application of a variety of resonance energy transfer techniques such as bioluminescence (BRET), fluorescence (FRET) and sequential energy transfer (SRET). The assembly of interacting GPCRs, heterodimers and receptor mosaic leads to changes in the agonist recognition, signaling, and trafficking of participating receptors via allosteric mechanisms, sometimes involving the appearance of cooperativity. The receptor interface in the GPCR heteromers is beginning to be characterized and the key role of electrostatic epitope-epitope interactions for the formation of the receptor heteromers will be discussed. Furthermore, a "guide-and-clasp" manner of receptor-receptor interactions has been proposed where the "adhesive guides" may be the triplet homologies. These interactions probably represent a general molecular mechanism for receptor-receptor interactions. It is proposed that changes in GPCR function (moonlighting) may develop through the intracellular loops and C-terminii of the GPCR heteromers as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptors. The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neurophysiology and neuropathology. Furthermore, novel therapeutic approaches could be possible based on the use of heteromers as targets for drug development based on their unique pharmacology.

Original languageEnglish (US)
Pages (from-to)356-363
Number of pages8
JournalCurrent Medicinal Chemistry
Issue number3
StatePublished - Jan 2012


  • Adenosine receptor
  • Allosteric modulation
  • Dopamine receptors
  • GPCR
  • Moonlighting
  • Oligomers
  • Receptor G protein coupling
  • Receptor interface
  • Receptor mosaic
  • Receptor recognition
  • Receptor signaling
  • Receptor trafficking
  • Triplet homologies

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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