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Rafael Franco - One of the best experts on this subject based on the ideXlab platform.
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structure of g protein coupled Receptor Heteromers
2020Co-Authors: Arnau Cordomi, Rafael Franco, Gemma Navarro, Leonardo PardoAbstract:Abstract G protein-coupled Receptors (GPCRs) form homo- and heterodimers and higher-level oligomers whose function is now just starting to be revealed. The current understanding on the structure of dimers and oligomers is gaining momentum despite more work being needed. In this chapter, we review the structural information currently available for GPCR homomers and Heteromers. We consider two main cases: (1) metabotropic glutamate (mGlu) Receptors (or class C), which have been demonstrated to form obligated dimers in vitro and from which the first homodimeric structures have just been reported, and (2) rhodopsinlike Receptors (class A), whose Heteromers have been described in natural sources. We review the progress made in the field in the recent years and the current challenges.
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neurochemical evidence supporting dopamine d1 d2 Receptor Heteromers in the striatum of the long tailed macaque changes following dopaminergic manipulation
Brain Structure & Function, 2017Co-Authors: Alberto J. Rico, Diego Sucunza, Diego Pignataro, Elvira Roda, Susan R. George, Iria G Dopesoreyes, Eva Martinezpinilla, David Marinramos, Jose L Labandeiragarcia, Rafael FrancoAbstract:Although it has long been widely accepted that dopamine Receptor types D1 and D2 form GPCR Heteromers in the striatum, the presence of D1–D2 Receptor Heteromers has been recently challenged. In an attempt to properly characterize D1–D2 Receptor Heteromers, here we have used the in situ proximity ligation assay (PLA) in striatal sections comprising the caudate nucleus, the putamen and the core and shell territories of the nucleus accumbens. Experiments were carried out in control macaques as well as in MPTP-treated animals (with and without dyskinesia). Obtained data support the presence of D1–D2 Receptor Heteromers within all the striatal subdivisions, with the highest abundance in the accumbens shell. Dopamine depletion by MPTP resulted in an increase of D1–D2 density in caudate and putamen which was normalized by levodopa treatment. Two different sizes of Heteromers were consistently found, thus suggesting that besides individual Heteromers, D1–D2 Receptor Heteromers are sometimes organized in macromolecular complexes made of a number of D1–D2 Heteromers. Furthermore, the PLA technique was combined with different neuronal markers to properly characterize the identities of striatal neurons expressing D1–D2 Heteromers. We have found that striatal projection neurons giving rise to either the direct or the indirect basal ganglia pathways expressed D1–D2 Heteromers. Interestingly, macromolecular complexes of D1–D2 Heteromers were only found within cholinergic interneurons. In summary, here we provide overwhelming proof that D1 and D2 Receptors form heteromeric complexes in the macaque striatum, thus representing a very appealing target for a number of brain diseases involving dopamine dysfunction.
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Neurochemical evidence supporting dopamine D1–D2 Receptor Heteromers in the striatum of the long-tailed macaque: changes following dopaminergic manipulation
Brain Structure and Function, 2017Co-Authors: Alberto J. Rico, Iria G. Dopeso-reyes, Diego Sucunza, Diego Pignataro, Elvira Roda, David Marín-ramos, José L. Labandeira-garcía, Eva Martínez-pinilla, Susan R. George, Rafael FrancoAbstract:Although it has long been widely accepted that dopamine Receptor types D1 and D2 form GPCR Heteromers in the striatum, the presence of D1–D2 Receptor Heteromers has been recently challenged. In an attempt to properly characterize D1–D2 Receptor Heteromers, here we have used the in situ proximity ligation assay (PLA) in striatal sections comprising the caudate nucleus, the putamen and the core and shell territories of the nucleus accumbens. Experiments were carried out in control macaques as well as in MPTP-treated animals (with and without dyskinesia). Obtained data support the presence of D1–D2 Receptor Heteromers within all the striatal subdivisions, with the highest abundance in the accumbens shell. Dopamine depletion by MPTP resulted in an increase of D1–D2 density in caudate and putamen which was normalized by levodopa treatment. Two different sizes of Heteromers were consistently found, thus suggesting that besides individual Heteromers, D1–D2 Receptor Heteromers are sometimes organized in macromolecular complexes made of a number of D1–D2 Heteromers. Furthermore, the PLA technique was combined with different neuronal markers to properly characterize the identities of striatal neurons expressing D1–D2 Heteromers. We have found that striatal projection neurons giving rise to either the direct or the indirect basal ganglia pathways expressed D1–D2 Heteromers. Interestingly, macromolecular complexes of D1–D2 Heteromers were only found within cholinergic interneurons. In summary, here we provide overwhelming proof that D1 and D2 Receptors form heteromeric complexes in the macaque striatum, thus representing a very appealing target for a number of brain diseases involving dopamine dysfunction.
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Detection of cannabinoid Receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism
Brain Structure and Function, 2015Co-Authors: Salvador Sierra, Natasha Luquin, Iria G. Dopeso-reyes, Elvira Roda, José L. Labandeira-garcía, Virginia Gómez-bautista, Alfonso Vázquez, Eva Martínez-pinilla, Alberto J. Rico, Rafael FrancoAbstract:Although type 1 cannabinoid Receptors (CB1Rs) are expressed abundantly throughout the brain, the presence of type 2 cannabinoid Receptors (CB2Rs) in neurons is still somewhat controversial. Taking advantage of newly designed CB1R and CB2R mRNA riboprobes, we demonstrate by PCR and in situ hybridization that transcripts for both cannabinoid Receptors are present within labeled pallidothalamic-projecting neurons of control and MPTP-treated macaques, whereas the expression is markedly reduced in dyskinetic animals. Moreover, an in situ proximity ligation assay was used to qualitatively assess the presence of CB1Rs and CB2Rs, as well as CB1R–CB2R Heteromers within basal ganglia output neurons in all animal groups (control, parkinsonian and dyskinetic macaques). A marked reduction in the number of CB1Rs, CB2Rs and CB1R–CB2R Heteromers was found in dyskinetic animals, mimicking the observed reduction in CB1R and CB2R mRNA expression levels. The fact that chronic levodopa treatment disrupted CB1R–CB2R heteromeric complexes should be taken into consideration when designing new drugs acting on cannabinoid Receptor Heteromers.
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Dopamine Receptor heteromeric complexes and their emerging functions.
Progress in Brain Research, 2014Co-Authors: Susan R. George, Andras Kern, Roy G. Smith, Rafael FrancoAbstract:Abstract Dopamine neurotransmission is traditionally accepted as occurring through the five dopamine Receptors that transduce its signal. Recent evidence has demonstrated that the range of physiologically relevant dopamine signaling complexes is greatly expanded by the ability of dopamine Receptors to interact with other dopamine Receptors and with Receptors of other endogenous signaling ligands. These novel heteromeric complexes have functional properties distinct from the component Receptors or are able to modulate the canonical signaling and function of the cognate Receptors. These dopamine Receptor Heteromers provide new insight into physiological mechanisms and pathophysiological processes involving dopamine.
Sergi Ferre - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH PAPER Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 Receptors
2020Co-Authors: Carla Ferrada, Enric I. Canela, Estefania Moreno, Josefa Mallol, Sergi Ferre, Vicent Casado, Antoni Cortes, Gerold Bongers, Rob Leurs, Carme LluisAbstract:Background and purpose: Functional interactions between the G protein-coupled dopamine D1 and histamine H3 Receptors have been described in the brain. In the present study we investigated the existence of D1–H3 Receptor Heteromers and their biochemical characteristics. Experimental approach: D1–H3 Receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen-activated protein kinase (MAPK) and adenylyl cyclase pathways was studied in co-transfected cells and compared with cells transfected with either D1 or H3 Receptors. Key results: Bioluminescence Resonance Energy Transfer and binding assays confirmed that D1 and H3 Receptors can heteromerize. Activation of histamine H3 Receptors did not lead to signalling towards the MAPK pathway unless dopamine D1 Receptors were co-expressed. Also, dopamine D1 Receptors, usually coupled to Gs proteins and leading to increases in cAMP, did not couple to Gs but to Gi in co-transfected cells. Furthermore, signalling via each Receptor was blocked not only by a selective antagonist but also by an antagonist of the partner Receptor. Conclusions and implications: D1–H3 Receptor Heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a Gs-independent and Gi-dependent manner. An antagonist of one of the Receptor units in the D1–H3 Receptor heteromer can induce conformational changes in the other Receptor unit and block specific signals originating in the heteromer. This gives rise to unsuspected therapeutic potentials for G protein-coupled Receptor antagonists. British Journal of Pharmacology (2009) 157, 64–75; doi:10.1111/j.1476-5381.2009.00152.x
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Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine.
Journal of Alzheimer's disease : JAD, 2020Co-Authors: Sergi FerreAbstract:Caffeine is the most consumed psychoactive drug in the world. It is a non-selective adenosine Receptor antagonist that in the brain targets mainly adenosine A1 and A2A Receptors. The same as classical psychostimulants, caffeine produces motor-activating, reinforcing and arousing effects. This depends on the ability of caffeine to counteract multiple effects of adenosine in the central ascending neurotransmitter systems. Motor and reinforcing effects depend on the ability of caffeine to release pre- and postsynaptic brakes that adenosine imposes on the ascending dopaminergic system. By targeting A1-A2A Receptor Heteromers in striatal glutamatergic terminals and A1 Receptors in striatal dopaminergic terminals (presynaptic brake), caffeine induces glutamate-dependent and glutamate-independent release of dopamine. These presynaptic effects of caffeine are potentiated by the release of the postsynaptic brake imposed by antagonistic interactions in the striatal A2A-D2 and A1-D1 Receptor Heteromers. Arousing effects of caffeine depend on the blockade of multiple inhibitory mechanisms that adenosine, as an endogenous sleep-promoting substance, exerts on the multiply interconnected ascending arousal systems. Those mechanisms include a direct A1-Receptor mediated modulation of the corticopetal basal forebrain system and an indirect A2A-Receptor mediated modulation of the hypothalamic histaminergic and orexinergic systems.
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Adenosine A_1-Dopamine D_1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron
Molecular Neurobiology, 2019Co-Authors: Marla Rivera-oliver, Enric I. Canela, Estefania Moreno, Sergi Ferre, Yocasta Álvarez-bagnarol, Christian Ayala-santiago, Nicole Cruz-reyes, Gian Carlo Molina-castro, Stefan Clemens, Vicent CasadoAbstract:While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine Receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A_1-dopamine D_1 Receptor Heteromers in the spinal motoneuron by which adenosine tonically inhibits D_1 Receptor-mediated signaling. A_1-D_1 Receptor Heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.
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adenosine a1 dopamine d1 Receptor Heteromers control the excitability of the spinal motoneuron
Molecular Neurobiology, 2019Co-Authors: Marla Riveraoliver, Enric I. Canela, Estefania Moreno, Sergi Ferre, Stefan Clemens, Yocasta Alvarezbagnarol, Christian Ayalasantiago, Nicole Cruzreyes, Gian Carlo Molinacastro, Vicent CasadoAbstract:While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine Receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A1-dopamine D1 Receptor Heteromers in the spinal motoneuron by which adenosine tonically inhibits D1 Receptor-mediated signaling. A1-D1 Receptor Heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.
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behavioral control by striatal adenosine a2a dopamine d2 Receptor Heteromers
Genes Brain and Behavior, 2018Co-Authors: Jaume Taura, Sergi Ferre, Marta Valleleon, Kristoffer Sahlholm, Masahiko Watanabe, K Van Craenenbroeck, Victor Fernandezduenas, Francisco CiruelaAbstract:G protein-coupled Receptors (GPCR) exhibit the ability to form Receptor complexes that include molecularly different GPCR (i.e. GPCR Heteromers), which endow them with singular functional and pharmacological characteristics. The relative expression of GPCR Heteromers remains a matter of intense debate. Recent studies support that adenosine A2A Receptors (A2AR) and dopamine D2 Receptors (D2R) predominantly form A2AR-D2R Heteromers in the striatum. The aim of the present study was evaluating the behavioral effects of pharmacological manipulation and genetic blockade of A2AR and D2R within the frame of such a predominant striatal heteromeric population. First, in order to avoid possible strain-related differences, a new D2R-deficient mouse with the same genetic background (CD-1) than the A2AR knock-out mouse was generated. Locomotor activity, pre-pulse inhibition (PPI) and drug-induced catalepsy were then evaluated in wild type, A2AR and D2R knockout mice, with and without the concomitant administration of either the D2R agonist sumanirole or the A2AR antagonist SCH442416. SCH442416-mediated locomotor effects were shown to be dependent on D2R signaling. Similarly, a significant dependence on A2AR signaling was observed for PPI and for haloperidol-induced catalepsy. The results could be explained by the existence of one main population of striatal postsynaptic A2AR-D2R Heteromers, which may constitute a relevant target for the treatment of Parkinson's disease and other neuropsychiatric disorders.
Estefania Moreno - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH PAPER Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 Receptors
2020Co-Authors: Carla Ferrada, Enric I. Canela, Estefania Moreno, Josefa Mallol, Sergi Ferre, Vicent Casado, Antoni Cortes, Gerold Bongers, Rob Leurs, Carme LluisAbstract:Background and purpose: Functional interactions between the G protein-coupled dopamine D1 and histamine H3 Receptors have been described in the brain. In the present study we investigated the existence of D1–H3 Receptor Heteromers and their biochemical characteristics. Experimental approach: D1–H3 Receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen-activated protein kinase (MAPK) and adenylyl cyclase pathways was studied in co-transfected cells and compared with cells transfected with either D1 or H3 Receptors. Key results: Bioluminescence Resonance Energy Transfer and binding assays confirmed that D1 and H3 Receptors can heteromerize. Activation of histamine H3 Receptors did not lead to signalling towards the MAPK pathway unless dopamine D1 Receptors were co-expressed. Also, dopamine D1 Receptors, usually coupled to Gs proteins and leading to increases in cAMP, did not couple to Gs but to Gi in co-transfected cells. Furthermore, signalling via each Receptor was blocked not only by a selective antagonist but also by an antagonist of the partner Receptor. Conclusions and implications: D1–H3 Receptor Heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a Gs-independent and Gi-dependent manner. An antagonist of one of the Receptor units in the D1–H3 Receptor heteromer can induce conformational changes in the other Receptor unit and block specific signals originating in the heteromer. This gives rise to unsuspected therapeutic potentials for G protein-coupled Receptor antagonists. British Journal of Pharmacology (2009) 157, 64–75; doi:10.1111/j.1476-5381.2009.00152.x
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Adenosine A_1-Dopamine D_1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron
Molecular Neurobiology, 2019Co-Authors: Marla Rivera-oliver, Enric I. Canela, Estefania Moreno, Sergi Ferre, Yocasta Álvarez-bagnarol, Christian Ayala-santiago, Nicole Cruz-reyes, Gian Carlo Molina-castro, Stefan Clemens, Vicent CasadoAbstract:While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine Receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A_1-dopamine D_1 Receptor Heteromers in the spinal motoneuron by which adenosine tonically inhibits D_1 Receptor-mediated signaling. A_1-D_1 Receptor Heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.
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adenosine a1 dopamine d1 Receptor Heteromers control the excitability of the spinal motoneuron
Molecular Neurobiology, 2019Co-Authors: Marla Riveraoliver, Enric I. Canela, Estefania Moreno, Sergi Ferre, Stefan Clemens, Yocasta Alvarezbagnarol, Christian Ayalasantiago, Nicole Cruzreyes, Gian Carlo Molinacastro, Vicent CasadoAbstract:While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine Receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A1-dopamine D1 Receptor Heteromers in the spinal motoneuron by which adenosine tonically inhibits D1 Receptor-mediated signaling. A1-D1 Receptor Heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.
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evidence for functional pre coupled complexes of Receptor Heteromers and adenylyl cyclase
Nature Communications, 2018Co-Authors: Gemma Navarro, Enric I. Canela, Estefania Moreno, Vicent Casado, Antoni Cortes, Arnau Cordomi, Leonardo Pardo, Veronica Casadoanguera, Carmen W Dessauer, Carme LluisAbstract:G protein-coupled Receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit. Using a peptide-based approach, we here report evidence for the existence of functional pre-coupled complexes of Heteromers of adenosine A2A Receptor and dopamine D2 Receptor homodimers coupled to their cognate Gs and Gi proteins and to subtype 5 AC. We also demonstrate that this macromolecular complex provides the necessary frame for the canonical Gs-Gi interactions at the AC level, sustaining the ability of a Gi-coupled GPCR to counteract AC activation mediated by a Gs-coupled GPCR. It is unclear whether GPCRs, G proteins and adenylyl cyclase (AC) associate through random collisions or defined pre-coupling mechanisms. Using a peptide-based approach, the authors show that Heteromers of adenosine A2A and dopamine D2 Receptors form pre-coupled complexes with their cognate G proteins and AC5.
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cannabis users show enhanced expression of cb1 5ht2a Receptor Heteromers in olfactory neuroepithelium cells
Molecular Neurobiology, 2018Co-Authors: L. Galindo, Estefania Moreno, D. Guinart, E. Menoyo, Cristina Fernández, Fernando Lopezarmenta, Aida Cuencaroyo, Merce Izquierdoserra, Laura Xicota, Jose M FernandezfernandezAbstract:Cannabinoid CB1 Receptors (CB1R) and serotonergic 2A Receptors (5HT2AR) form Heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CB1R-5HT2AR Heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na+ currents in patch clamp recordings. Interestingly, CB1R-5HT2AR heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB1R-5HT2AR Heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.
Vicent Casado - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH PAPER Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 Receptors
2020Co-Authors: Carla Ferrada, Enric I. Canela, Estefania Moreno, Josefa Mallol, Sergi Ferre, Vicent Casado, Antoni Cortes, Gerold Bongers, Rob Leurs, Carme LluisAbstract:Background and purpose: Functional interactions between the G protein-coupled dopamine D1 and histamine H3 Receptors have been described in the brain. In the present study we investigated the existence of D1–H3 Receptor Heteromers and their biochemical characteristics. Experimental approach: D1–H3 Receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen-activated protein kinase (MAPK) and adenylyl cyclase pathways was studied in co-transfected cells and compared with cells transfected with either D1 or H3 Receptors. Key results: Bioluminescence Resonance Energy Transfer and binding assays confirmed that D1 and H3 Receptors can heteromerize. Activation of histamine H3 Receptors did not lead to signalling towards the MAPK pathway unless dopamine D1 Receptors were co-expressed. Also, dopamine D1 Receptors, usually coupled to Gs proteins and leading to increases in cAMP, did not couple to Gs but to Gi in co-transfected cells. Furthermore, signalling via each Receptor was blocked not only by a selective antagonist but also by an antagonist of the partner Receptor. Conclusions and implications: D1–H3 Receptor Heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a Gs-independent and Gi-dependent manner. An antagonist of one of the Receptor units in the D1–H3 Receptor heteromer can induce conformational changes in the other Receptor unit and block specific signals originating in the heteromer. This gives rise to unsuspected therapeutic potentials for G protein-coupled Receptor antagonists. British Journal of Pharmacology (2009) 157, 64–75; doi:10.1111/j.1476-5381.2009.00152.x
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Adenosine A_1-Dopamine D_1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron
Molecular Neurobiology, 2019Co-Authors: Marla Rivera-oliver, Enric I. Canela, Estefania Moreno, Sergi Ferre, Yocasta Álvarez-bagnarol, Christian Ayala-santiago, Nicole Cruz-reyes, Gian Carlo Molina-castro, Stefan Clemens, Vicent CasadoAbstract:While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine Receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A_1-dopamine D_1 Receptor Heteromers in the spinal motoneuron by which adenosine tonically inhibits D_1 Receptor-mediated signaling. A_1-D_1 Receptor Heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.
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adenosine a1 dopamine d1 Receptor Heteromers control the excitability of the spinal motoneuron
Molecular Neurobiology, 2019Co-Authors: Marla Riveraoliver, Enric I. Canela, Estefania Moreno, Sergi Ferre, Stefan Clemens, Yocasta Alvarezbagnarol, Christian Ayalasantiago, Nicole Cruzreyes, Gian Carlo Molinacastro, Vicent CasadoAbstract:While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine Receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A1-dopamine D1 Receptor Heteromers in the spinal motoneuron by which adenosine tonically inhibits D1 Receptor-mediated signaling. A1-D1 Receptor Heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.
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evidence for functional pre coupled complexes of Receptor Heteromers and adenylyl cyclase
Nature Communications, 2018Co-Authors: Gemma Navarro, Enric I. Canela, Estefania Moreno, Vicent Casado, Antoni Cortes, Arnau Cordomi, Leonardo Pardo, Veronica Casadoanguera, Carmen W Dessauer, Carme LluisAbstract:G protein-coupled Receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit. Using a peptide-based approach, we here report evidence for the existence of functional pre-coupled complexes of Heteromers of adenosine A2A Receptor and dopamine D2 Receptor homodimers coupled to their cognate Gs and Gi proteins and to subtype 5 AC. We also demonstrate that this macromolecular complex provides the necessary frame for the canonical Gs-Gi interactions at the AC level, sustaining the ability of a Gi-coupled GPCR to counteract AC activation mediated by a Gs-coupled GPCR. It is unclear whether GPCRs, G proteins and adenylyl cyclase (AC) associate through random collisions or defined pre-coupling mechanisms. Using a peptide-based approach, the authors show that Heteromers of adenosine A2A and dopamine D2 Receptors form pre-coupled complexes with their cognate G proteins and AC5.
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CB1-5-HT2A Heteromers in schizophrenia patients: Human studies in pro-neurons of the olfactory epithelium
European Psychiatry, 2017Co-Authors: L. Galindo, Estefania Moreno, Patricia Robledo, D. Guinart, E.j. Pérez, Aida Cuenca-royo, E. Menoyo, Cristina Fernández, J. Garcia, Vicent CasadoAbstract:Introduction Despite multiple clinical and preclinical studies investigating schizophrenia, the neurobiological basis of this disease is still unknown. The dysregulation of the serotonergic system, in particular the 5-HT2A Receptor and the endocannabinoid system have been postulated as possible causes of schizophrenia. Objectives The aim of this study is to evaluate the expression of CB1-5-HT2A Receptor Heteromers in primary cultures of pro-neurons from the olfactory epithelium in schizophrenia patients and control subjects. Methods We recruited a group of 10 healthy volunteers and 10 patients diagnosed with schizophrenia, who were treated with atypical antipsychotics, were clinically stable and had an illness duration range from 1 up to 15 years. The patients were diagnosed with schizophrenia from the medical record and confirmed by the structured clinical interview for DSM disorders. The expression of CB1-5-HT2A Receptor Heteromers in primary cultures of pro-neurons from the olfactory epithelium was quantified using proximity ligation assays and confocal microscopy. Results Olfactory epithelium pro-neurons were viable and expressed the neuronal marker, III-β tubulin. We also established the presence and the functionality of CB1-5-HT2A Receptor Heteromers in these cells using the proximity ligation and cAMP activity assays, respectively. Heteromer expression was significantly increased in schizophrenia patients with respect to controls. Conclusions This highly innovative methodology will allow the noninvasive, low-cost study of new biomarkers for schizophrenia in a model closely related to the central nervous system.
Kjell Fuxe - One of the best experts on this subject based on the ideXlab platform.
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adenosine a2a d2 Receptor Receptor interactions in putative Heteromers in the regulation of the striato pallidal gaba pathway possible relevance for parkinson s disease and its treatment
Current Protein & Peptide Science, 2014Co-Authors: Sarah Beggiato, Luigi F Agnati, Kjell Fuxe, Tiziana Antonelli, Maria Cristina Tomasini, Andrea Celeste Borelli, Sergio Tanganelli, Luca FerraroAbstract:Striatal dopamine adenosine A2A and D2 Receptors interact to modulate some aspects of motor and motivational function. The demonstration of A2A/D2 Receptor heteromerization in living cells constituted a progress for understanding the neurobiology of dopamine D2 and adenosine A2A Receptors. In fact, the existence of putative striatalA2A/D2 Receptor Heteromers has been suggested to be important for striatal function under both normal and pathological conditions, such as Parkinson’s disease. Consequently, the antagonistic A2A-D2 Receptor interactions in a putative striatal Receptor heteromer on striato-pallidal GABA neuron led to the introduction of A2A Receptor antagonists as possible anti- Parkinsonian drugs. The present mini-review briefly summarizes the main findings supporting the presence of antagonistic A2A-D2 Receptor interactions in putative Receptor Heteromers in the basal ganglia. Special emphasis is given to in vivo microdialysis findings demonstrating the functional role putative A2A/D2 Heteromers on striato-pallidal GABA neurons play in the modulation of this pathway, in which A2A Receptors inhibit D2 Receptor signaling. The possible relevance of compounds targeting the putative striatal A2A/D2 heteromer in the Parkinson’s disease pharmacological treatment is also discussed.
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The impact of Receptor-Receptor interactions in heteroReceptor complexes on brain plasticity.
Expert Review of Neurotherapeutics, 2014Co-Authors: Kjell Fuxe, Luigi F Agnati, Dasiel O. Borroto-escuelaAbstract:Allosteric mechanisms in Receptor Heteromers markedly increase the repertoire of Receptor recognition and signaling. Of high importance is the altered function in the Receptor heteromer versus the Receptor homomer. Such a change in Receptor function is mainly brought about by agonist induced allosteric Receptor–Receptor interactions and leads to functional and structural plasticity. Receptor–Receptor interactions integrating synaptic and volume transmission signals participate in a significant way in modulating bidirectional synaptic plasticity and thus Hebbian plasticity. One molecular mechanism that can contribute to a change of synaptic weight may be represented by multiple interactions between plasma membrane Receptors forming higher order heteroReceptor complexes via oligomerization at the pre- and post-junctional level. Such long-lived heteroReceptor complexes may play a significant role in learning and memory.
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evidence for the existence of dopamine d2 oxytocin Receptor Heteromers in the ventral and dorsal striatum with facilitatory Receptor Receptor interactions
Molecular Psychiatry, 2013Co-Authors: Wilber Romerofernandez, Luigi F Agnati, Dasiel O Borrotoescuela, Kjell FuxeAbstract:Evidence for the existence of dopamine d2-oxytocin Receptor Heteromers in the ventral and dorsal striatum with facilitatory Receptor–Receptor interactions
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on the g protein coupled Receptor Heteromers and their allosteric Receptor Receptor interactions in the central nervous system focus on their role in pain modulation
Evidence-based Complementary and Alternative Medicine, 2013Co-Authors: Dasiel O Borrotoescuela, Luigi F Agnati, Alexander O Tarakanov, Wilber Romerofernandez, Alicia Rivera, Kathleen Van Craenenbroeck, Kjell FuxeAbstract:The modulatory role of allosteric Receptor-Receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid Receptor Heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid Receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid Receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating via β-arrestin2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid Receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide Receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin Receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia.
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integrin triplets of marine sponges in the murine and human mhci cd8 interface and in the interface of human neural Receptor Heteromers and subunits
SpringerPlus, 2013Co-Authors: Alexander O Tarakanov, Kjell FuxeAbstract:Based on our theory, main triplets of amino acid residues have been discovered in cell-adhesion Receptors (integrins) of marine sponges, which participate as homologies in the interface between two major immune molecules, MHC class I (MHCI) and CD8αβ. They appear as homologies also in several human neural Receptor Heteromers and subunits. The obtained results probably mean that neural and immune Receptors also utilize these structural integrin triplets to form Heteromers and ion channels, which are required for a tuned and integrated intracellular and intercellular communication and a communication between cells and the extracellular matrix with an origin in sponges, the oldest multicellular animals.
