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.
- Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS.
Borroto-Escuela DO, Fuxe K
Front Mol Neurosci, 25 September 2019;12():230
- Mapping the Interface of a GPCR Dimer: A Structural Model of the A2A Adenosine and D2 Dopamine Receptor Heteromer.
Borroto-Escuela DO, Rodriguez D, Romero-Fernandez W, Kapla J, Jaiteh M, Ranganathan A, et al
Front Pharmacol, 30 August 2018;9():829
- Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease.
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.
- Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine.
Wydra K, Gawliński D, Gawlińska K, Frankowska M, Borroto-Escuela DO, Fuxe K, et al
Cells, 1 June 2020;9(6):
- OSU-6162, a Sigma1R Ligand in Low Doses, Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes.
Borroto-Escuela DO, Romero-Fernandez W, Wydra K, Zhou Z, Suder A, Filip M, et al
Neurotox Res, February 2020;37(2):433-444
- A2AR Transmembrane 2 Peptide Administration Disrupts the A2AR-A2AR Homoreceptor but Not the A2AR-D2R Heteroreceptor Complex: Lack of Actions on Rodent Cocaine Self-Administration.
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):
- Heterodimerization of Mu Opioid Receptor Protomer with Dopamine D2 Receptor Modulates Agonist-Induced Internalization of Mu Opioid Receptor.
Vasudevan L, Borroto-Escuela DO, Huysentruyt J, Fuxe K, Saini DK, Stove C
Biomolecules, 14 August 2019;9(8):
- A2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction.
Borroto-Escuela DO, Wydra K, Filip M, Fuxe K
Trends Pharmacol. Sci., December 2018;39(12):1008-1020
- Disruption of A2AR-D2R Heteroreceptor Complexes After A2AR Transmembrane 5 Peptide Administration Enhances Cocaine Self-Administration in Rats.
Borroto-Escuela DO, Wydra K, Li X, Rodriguez D, Carlsson J, Jastrzębska J, et al
Mol. Neurobiol., August 2018;55(8):7038-7048
- Dopamine D4 receptor stimulation prevents nigrostriatal dopamine pathway activation by morphine: relevance for drug addiction.
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.
- Existence of FGFR1-5-HT1AR heteroreceptor complexes in hippocampal astrocytes. Putative link to 5-HT and FGF2 modulation of hippocampal gamma oscillations.
Narváez M, Andrade-Talavera Y, Valladolid-Acebes I, Fredriksson M, Siegele P, Hernandez-Sosa A, et al
Neuropharmacology 15 June 2020;170():108070
- Attenuation of Oxytocin and Serotonin 2A Receptor Signaling through Novel Heteroreceptor Formation.
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
- Disturbances in the FGFR1-5-HT1A Heteroreceptor Complexes in the Raphe-Hippocampal 5-HT System Develop in a Genetic Rat Model of Depression.
Borroto-Escuela DO, DuPont CM, Li X, Savelli D, Lattanzi D, Srivastava I, et al
Front Cell Neurosci, 10 October 2017;11():309
- Existence of Brain 5-HT1A-5-HT2A Isoreceptor Complexes with Antagonistic Allosteric Receptor-Receptor Interactions Regulating 5-HT1A Receptor Recognition.
Borroto-Escuela DO, Li X, Tarakanov AO, Savelli D, Narváez M, Shumilov K, et al
ACS Omega 31 August 2017;2(8):4779-4789
- Receptor⁻Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment.
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 distinc 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.
- Conventional and Novel Pharmacological Approaches to Treat Dopamine-Related Disorders: Focus on Parkinson's Disease and Schizophrenia.
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
- Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia.
Borroto-Escuela DO, Ferraro L, Narvaez M, Tanganelli S, Beggiato S, Liu F, et al
Cells, 27 April 2020;9(5):
- IL1R2, CCR2, and CXCR4 May Form Heteroreceptor Complexes with NMDAR and D2R: Relevance for Schizophrenia.
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.
- Conventional and Novel Pharmacological Approaches to Treat Dopamine-Related Disorders: Focus on Parkinson's Disease and Schizophrenia.
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
- Adenosine heteroreceptor complexes in the basal ganglia are implicated in Parkinson's disease and its treatment.
Borroto-Escuela DO, Fuxe K
J Neural Transm (Vienna), April 2019;126(4):455-471
- Brain Dopamine Transmission in Health and Parkinson's Disease: Modulation of Synaptic Transmission and Plasticity Through Volume Transmission and Dopamine Heteroreceptors.
Borroto-Escuela DO, Perez De La Mora M, Manger P, Narváez M, Beggiato S, Crespo-Ramírez M, et al
Front Synaptic Neurosci, 10 July 2018;10():20
- Understanding the Role of Adenosine A2AR Heteroreceptor Complexes in Neurodegeneration and Neuroinflammation.
Borroto-Escuela DO, Hinz S, Navarro G, Franco R, Müller CE, Fuxe K
Front Neurosci, 6 February 2018;12():43