On the existence of multiple A2A, D2 and sigma1 allosteric receptor–receptor interactions in sigma1–D2 and A2A–D2–sigma1 heteroreceptor complexes: role in brain plasticity and cocaine actions

2016 ◽  
Vol 4 (Suppl. 2) ◽  
pp. A13.2
Author(s):  
Dasiel O. Borroto-Escuela
Keyword(s):  
Brain Plasticity ◽  
Heteroreceptor Complexes ◽  
Receptor Interactions

The impact of receptor–receptor interactions in heteroreceptor complexes on brain plasticity

2014 ◽  
Vol 14 (7) ◽  
pp. 719-721 ◽  
Author(s):  
Kjell Fuxe ◽  
Luigi F Agnati ◽  
Dasiel O Borroto-Escuela
Keyword(s):  
Brain Plasticity ◽  
Heteroreceptor Complexes ◽  
Receptor Interactions ◽  
The Impact

scholarly journals Diversity and Bias through Receptor–Receptor Interactions in GPCR Heteroreceptor Complexes. Focus on Examples from Dopamine D2 Receptor Heteromerization

2014 ◽  
Vol 5 ◽  
Author(s):  
Kjell Fuxe ◽  
Alexander Tarakanov ◽  
Wilber Romero Fernandez ◽  
Luca Ferraro ◽  
Sergio Tanganelli ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Heteroreceptor Complexes ◽  
Dopamine D2 ◽  
Receptor Interactions

Dopamine D2 heteroreceptor complexes and their receptor–receptor interactions in ventral striatum

2014 ◽  
pp. 113-139 ◽  
Author(s):  
Kjell Fuxe ◽  
Dasiel O. Borroto-Escuela ◽  
Alexander O. Tarakanov ◽  
Wilber Romero-Fernandez ◽  
Luca Ferraro ◽  
...  
Keyword(s):  
Ventral Striatum ◽  
Heteroreceptor Complexes ◽  
Dopamine D2 ◽  
Receptor Interactions

scholarly journals SY28-5RECEPTOR-RECEPTOR INTERACTIONS IN HETERORECEPTOR COMPLEXES. A NEW CONCEPT IN NEUROPSYCHOPHARMACOLOGY

2015 ◽  
Vol 50 (suppl 1) ◽  
pp. i32.1-i32
Author(s):  
K. Fuxe ◽  
A. Hansson ◽  
D. O. Borroto-Escuela
Keyword(s):  
Heteroreceptor Complexes ◽  
Receptor Interactions

scholarly journals Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1902
Author(s):  
Dasiel O. Borroto-Escuela ◽  
Patrizia Ambrogini ◽  
Manuel Narvaez ◽  
Valentina Di Liberto ◽  
Sarah Beggiato ◽  
...  
Keyword(s):  
Mental Disease ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Positive Effects ◽  
Heteroreceptor Complexes ◽  
Receptor Interactions ◽  
Mental Diseases ◽  
Biological Principle ◽  
Serotonin Neurons ◽  
Allosteric Mechanisms

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.

scholarly journals Understanding the Functional Plasticity in Neural Networks of the Basal Ganglia in Cocaine Use Disorder: A Role for Allosteric Receptor-Receptor Interactions in A2A-D2 Heteroreceptor Complexes

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Dasiel O. Borroto-Escuela ◽  
Karolina Wydra ◽  
Julia Pintsuk ◽  
Manuel Narvaez ◽  
Fidel Corrales ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Neural Plasticity ◽  
Molecular Basis ◽  
Dorsal Striatum ◽  
Self Administration ◽  
Heteroreceptor Complexes ◽  
Gaba Neurons ◽  
Cocaine Seeking ◽  
Receptor Interactions ◽  
Reward Motivation

Our hypothesis is that allosteric receptor-receptor interactions in homo- and heteroreceptor complexes may form the molecular basis of learning and memory. This principle is illustrated by showing how cocaine abuse can alter the adenosine A2AR-dopamine D2R heterocomplexes and their receptor-receptor interactions and hereby induce neural plasticity in the basal ganglia. Studies with A2AR ligands using cocaine self-administration procedures indicate that antagonistic allosteric A2AR-D2R heterocomplexes of the ventral striatopallidal GABA antireward pathway play a significant role in reducing cocaine induced reward, motivation, and cocaine seeking. Anticocaine actions of A2AR agonists can also be produced at A2AR homocomplexes in these antireward neurons, actions in which are independent of D2R signaling. At the A2AR-D2R heterocomplex, they are dependent on the strength of the antagonistic allosteric A2AR-D2R interaction and the number of A2AR-D2R and A2AR-D2R-sigma1R heterocomplexes present in the ventral striatopallidal GABA neurons. It involves a differential cocaine-induced increase in sigma1Rs in the ventral versus the dorsal striatum. In contrast, the allosteric brake on the D2R protomer signaling in the A2AR-D2R heterocomplex of the dorsal striatopallidal GABA neurons is lost upon cocaine self-administration. This is potentially due to differences in composition and allosteric plasticity of these complexes versus those in the ventral striatopallidal neurons.

scholarly journals Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1077
Author(s):  
Dasiel O. Borroto-Escuela ◽  
Luca Ferraro ◽  
Manuel Narvaez ◽  
Sergio Tanganelli ◽  
Sarah Beggiato ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Receptor Complexes ◽  
Heteroreceptor Complexes ◽  
A2a Receptor ◽  
Receptor Interactions ◽  
Relevant Role ◽  
The Central Nervous System ◽  
Adenosine A2a ◽  
The Brain

In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor–receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine–dopamine heteroreceptor complexes were identified that lead to the A2A-D2 heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A2A-D2 receptor–receptor interactions and their presence in the ventral striato-pallidal GABA anti-reward neurons leading to reduction of positive symptoms. Other types of adenosine A2A heteroreceptor complexes are also discussed in relation to this disease, such as A2A-D3 and A2A-D4 heteroreceptor complexes as well as higher order A2A-D2-mGluR5 and A2A-D2-Sigma1R heteroreceptor complexes. The A2A receptor protomer can likely modulate the function of the D4 receptors of relevance for understanding cognitive dysfunction in schizophrenia. A2A-D2-mGluR5 complex is of interest since upon A2A/mGluR5 coactivation they appear to synergize in producing strong inhibition of the D2 receptor protomer. For understanding the future of the schizophrenia treatment, the vulnerability of the current A2A-D2like receptor complexes will be tested in animal models of schizophrenia. A2A-D2-Simag1R complexes hold the highest promise through Sigma1R enhancement of inhibition of D2R function. In line with this work, Lara proposed a highly relevant role of adenosine for neurobiology of schizophrenia.

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