The introduction of the concept of direct physical receptor-receptor interactions in the plasma membrane originated from biochemical receptor binding studies showing that neuropeptides can modulate the affinity and density of monoamine receptors in membrane preparations in the early 1980s. These results indicated the existence of neuropeptide-monoamine receptor-receptor interactions in the plasma membrane. The first meeting on receptor-receptor interactions was held in Stockholm in 1986 (the organizers were Kjell Fuxe and Luigi Agnati). The proceedings were published in 1987. In 1993 the allosteric receptor-receptor interactions were proposed to take place in heterodimers in balance with homodimers (Zoli et al.1993, Mol. Neurobiol. 7,294-394).
The concept of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) homo- and heteroreceptor complexes, in which they physically interact provides a new dimension to molecular integration in the brain. The receptor-receptor interactions dynamically change recognition, pharmacology, signaling and trafficking of the participating receptors and thus their function.
We introduced a novel hypothesis that vulnerability of distinct GPCR heteroreceptor complexes can be a major cause for brain disorders involving dramatic dysfunction through mark changes in their densities and allosteric receptor-receptor interactions.
Recent work
Fundamental concepts
Concepts introduced by our group on GPCR heteroreceptor complexes and their integrative receptor-receptor interactions in the CNS for understanding brain integration and providing novel treatments of brain disease.
Borroto-Escuela DO, Fuxe K
Front Mol Neurosci, 25 September 2019;12():230
Borroto-Escuela DO, Rodriguez D, Romero-Fernandez W, Kapla J, Jaiteh M, Ranganathan A, et al
Front Pharmacol, 30 August 2018;9():829
Borroto-Escuela DO, Carlsson J, Ambrogini P, Narváez M, Wydra K, Tarakanov AO, et al
Front Cell Neurosci, 21 February 2017 ;11():37
Cocaine and morphine addiction
Understanding integrative molecular mechanisms involving especially A2AR-D2R heteroreceptor complexes and their receptor-receptor interactions but also MOR-D2likeR heteroreceptor complexes.
It will help elucidate cocaine and morphine addiction and open up novel treatment options of these types of addiction.
Wydra K, Gawliński D, Gawlińska K, Frankowska M, Borroto-Escuela DO, Fuxe K, et al
Cells, 1 June 2020;9(6):
Borroto-Escuela DO, Romero-Fernandez W, Wydra K, Zhou Z, Suder A, Filip M, et al
Neurotox Res, February 2020;37(2):433-444
Borroto-Escuela DO, Wydra K, Romero-Fernandez W, Zhou Z, Frankowska M, Filip M, et al
Int J Mol Sci, 3 December 2019;20(23):
Vasudevan L, Borroto-Escuela DO, Huysentruyt J, Fuxe K, Saini DK, Stove C
Biomolecules, 14 August 2019;9(8):
Borroto-Escuela DO, Wydra K, Filip M, Fuxe K
Trends Pharmacol. Sci., December 2018;39(12):1008-1020
Borroto-Escuela DO, Wydra K, Li X, Rodriguez D, Carlsson J, Jastrzębska J, et al
Mol. Neurobiol., August 2018;55(8):7038-7048
Rivera A, Gago B, Suárez-Boomgaard D, Yoshitake T, Roales-Buján R, Valderrama-Carvajal A, et al
Addict Biol, September 2017;22(5):1232-124
Depression
Understanding integrative molecular mechanisms involving especially FGFR1-5-HT1A heteroreceptor complexes and their receptor-receptor interactions but also 5-HT1A-5-HT2A and other 5-HT1A and also oxytocin heteroreceptor complexes.
This research may help us understand depression and provide novel, antidepressant drugs, especially of treatment resistant depression.
Narváez M, Andrade-Talavera Y, Valladolid-Acebes I, Fredriksson M, Siegele P, Hernandez-Sosa A, et al
Neuropharmacology 15 June 2020;170():108070
Chruścicka B, Wallace Fitzsimons SE, Borroto-Escuela DO, Druelle C, Stamou P, Nally K, et al
ACS Chem Neurosci, 17 July 2019;10(7):3225-3240
Borroto-Escuela DO, DuPont CM, Li X, Savelli D, Lattanzi D, Srivastava I, et al
Front Cell Neurosci, 10 October 2017;11():309
Borroto-Escuela DO, Li X, Tarakanov AO, Savelli D, Narváez M, Shumilov K, et al
ACS Omega 31 August 2017;2(8):4779-4789
Borroto-Escuela DO, Narváez M, Ambrogini P, Ferraro L, Brito I, Romero-Fernandez W, et al
Molecules, 3 June 2018;23(6):
Schizophrenia
Understanding integrative molecular mechanisms involving especially A2AR-D2R heteroreceptor complexes and their receptor-receptor interactions in ventral striatum in relation to schizophrenia.
The role of distinct immune receptors and their potential physical interactions with NMDAR and D2R are also proposed to play a significant role in schizophrenia.
This research has led to the A2AR hypothesis of schizophrenia with A2AR-D2R complexes having a significant role. Targeting these complexes may lead to development of novel antipsychotic drugs.
Perez de la Mora M, Hernandez-Mondragon C, Crespo-Ramirez M, Rejon-Orantes J, Borroto-Escuela DO, Fuxe K
Neuroscience, 15 July 2020;439():301-318
Borroto-Escuela DO, Ferraro L, Narvaez M, Tanganelli S, Beggiato S, Liu F, et al
Cells, 27 April 2020;9(5):
Borroto-Escuela DO, Tarakanov AO, Bechter K, Fuxe K
Front Psychiatry 15 February 2017;8():24
Parkinson's disease
Understanding integrative molecular mechanisms involving especially A2AR-D2R heteroreceptor complexes and their receptor-receptor interactions in dorsal striatum is of high relevance to see what goes wrong in sensory-motor integration in Parkinson’s disease.
This research has led to the hypothesis that disturbances in A2AR-D2R, A2AR-mGluR5 and A2AR-D2R-mGluR5 complexes have a significant role in Parkinson’s disease by enhancing the brake in motor activation. It is produced through overactivity in the dorsal striato-pallidal GABA pathway induced by inhibition of the inhibitory D2R function in the receptor complexes present in this pathway.
Targeting these complexes may lead to development of novel antiparkinsonian drugs.
Perez de la Mora M, Hernandez-Mondragon C, Crespo-Ramirez M, Rejon-Orantes J, Borroto-Escuela DO, Fuxe K
Neuroscience, 15 July 2020;439():301-318
Borroto-Escuela DO, Fuxe K
J Neural Transm (Vienna), April 2019;126(4):455-471
Borroto-Escuela DO, Perez De La Mora M, Manger P, Narváez M, Beggiato S, Crespo-RamÃrez M, et al
Front Synaptic Neurosci, 10 July 2018;10():20
Borroto-Escuela DO, Hinz S, Navarro G, Franco R, Müller CE, Fuxe K
Front Neurosci, 6 February 2018;12():43