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Nigel Taylor - One of the best experts on this subject based on the ideXlab platform.
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Cassava shrunken-2 homolog MeAPL3 determines storage root starch and dry matter content and modulates storage root postharvest physiological deterioration
Plant Molecular Biology, 2020Co-Authors: Getu Beyene, Raj Deepika Chauhan, Jackson Gehan, Dimuth Siritunga, Nigel TaylorAbstract:Key message Among the five cassava isoforms ( MeAPL1 – MeAPL5 ), MeAPL3 is responsible for determining storage root starch content. Degree of storage root postharvest physiological deterioration (PPD) is directly correlated with starch content. Abstract AGPase is Heterotetramer composed of two small and two large subunits each coded by small gene families in higher plants. Studies in cassava ( M anihot e sculenta ) identified and characterized five isoforms of M anihot e sculenta A DP-glucose p yrophosphorylase l arge subunit ( MeAPL1 – MeAPL5 ) and employed virus induced gene silencing (VIGS) to show that MeAPL3 is the key isoform responsible for starch and dry matter accumulation in cassava storage roots. Silencing of MeAPL3 in cassava through stable transgenic lines resulted in plants displaying significant reduction in storage root starch and dry matter content (DMC) and induced a distinct phenotype associated with increased petiole/stem angle, resulting in a droopy leaf phenotype. Plants with reduced starch and DMC also displayed significantly reduced or no postharvest physiological deterioration (PPD) compared to controls and lines with high DMC and starch content. This provides strong evidence for direct relationships between starch/dry matter content and its role in PPD and canopy architecture traits in cassava.
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Cassava shrunken-2 homolog MeAPL3 determines storage root starch and dry matter content and modulates storage root postharvest physiological deterioration
Plant Molecular Biology, 2020Co-Authors: Getu Beyene, Raj Deepika Chauhan, Jackson Gehan, Dimuth Siritunga, Nigel TaylorAbstract:Key message Among the five cassava isoforms ( MeAPL1 – MeAPL5 ), MeAPL3 is responsible for determining storage root starch content. Degree of storage root postharvest physiological deterioration (PPD) is directly correlated with starch content. Abstract AGPase is Heterotetramer composed of two small and two large subunits each coded by small gene families in higher plants. Studies in cassava ( M anihot e sculenta ) identified and characterized five isoforms of M anihot e sculenta A DP-glucose p yrophosphorylase l arge subunit ( MeAPL1 – MeAPL5 ) and employed virus induced gene silencing (VIGS) to show that MeAPL3 is the key isoform responsible for starch and dry matter accumulation in cassava storage roots. Silencing of MeAPL3 in cassava through stable transgenic lines resulted in plants displaying significant reduction in storage root starch and dry matter content (DMC) and induced a distinct phenotype associated with increased petiole/stem angle, resulting in a droopy leaf phenotype. Plants with reduced starch and DMC also displayed significantly reduced or no postharvest physiological deterioration (PPD) compared to controls and lines with high DMC and starch content. This provides strong evidence for direct relationships between starch/dry matter content and its role in PPD and canopy architecture traits in cassava.
David M Waisman - One of the best experts on this subject based on the ideXlab platform.
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annexin a2 Heterotetramer structure and function
International Journal of Molecular Sciences, 2013Co-Authors: Alamelu G Bharadwaj, Moamen Bydoun, Ryan W Holloway, David M WaismanAbstract:Annexin A2 is a pleiotropic calcium- and anionic phospholipid-binding protein that exists as a monomer and as a Heterotetrameric complex with the plasminogen receptor protein, S100A10. Annexin A2 has been proposed to play a key role in many processes including exocytosis, endocytosis, membrane organization, ion channel conductance, and also to link F-actin cytoskeleton to the plasma membrane. Despite an impressive list of potential binding partners and regulatory activities, it was somewhat unexpected that the annexin A2-null mouse should show a relatively benign phenotype. Studies with the annexin A2-null mouse have suggested important functions for annexin A2 and the Heterotetramer in fibrinolysis, in the regulation of the LDL receptor and in cellular redox regulation. However, the demonstration that depletion of annexin A2 causes the depletion of several other proteins including S100A10, fascin and affects the expression of at least sixty-one genes has confounded the reports of its function. In this review we will discuss the annexin A2 structure and function and its proposed physiological and pathological roles.
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the role of the annexin a2 Heterotetramer in vascular fibrinolysis
Blood, 2011Co-Authors: Patricia A Madureira, Alexi P Surette, Kyle D Phipps, Michael A S Taboski, Victoria A Miller, David M WaismanAbstract:The vascular endothelial cells line the inner surface of blood vessels and function to maintain blood fluidity by producing the protease plasmin that removes blood clots from the vasculature, a process called fibrinolysis. Plasminogen receptors play a central role in the regulation of plasmin activity. The protein complex annexin A2 Heterotetramer (AIIt) is an important plasminogen receptor at the surface of the endothelial cell. AIIt is composed of 2 molecules of annexin A2 (ANXA2) bound together by a dimer of the protein S100A10. Recent work performed by our laboratory allowed us to clarify the specific roles played by ANXA2 and S100A10 subunits within the AIIt complex, which has been the subject of debate for many years. The ANXA2 subunit of AIIt functions to stabilize and anchor S100A10 to the plasma membrane, whereas the S100A10 subunit initiates the fibrinolytic cascade by colocalizing with the urokinase type plasminogen activator and receptor complex and also providing a common binding site for both tissue-type plasminogen activator and plasminogen via its C-terminal lysine residue. The AIIt mediated colocalization of the plasminogen activators with plasminogen results in the rapid and localized generation of plasmin to the endothelial cell surface, thereby regulating fibrinolysis.
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annexin a2 s100a10 Heterotetramer a novel substrate of thioredoxin
Journal of Biological Chemistry, 2005Co-Authors: Mijung Kwon, Changsoon Yoon, Woojin Jeong, Sue Goo Rhee, David M WaismanAbstract:Abstract The binding of plasminogen activators and plasminogen to the cell surface results in the rapid generation of the serine protease plasmin. Plasmin is further degraded by an autoproteolytic reaction, resulting in the release of an angiostatin, A61 (Lys78–Lys468). Previously, we demonstrated that the annexin A2-S100A10 Heterotetramer (AIIt) stimulates the release of A61 from plasmin by promoting the autoproteolytic cleavage of the Lys468–Gly469 bond and reduction of the plasmin Cys462–Cys541 disulfide (Kwon, M., Caplan, J. F., Filipenko, N. R., Choi, K. S., Fitzpatrick, S. L., Zhang, L., and Waisman, D. M. (2002) J. Biol. Chem. 277, 10903–10911). Mechanistically, it was unclear if AIIt promoted a conformational change in plasmin, resulting in contortion of the plasmin disulfide, or directly reduced the plasmin disulfide. In the present study, we show that AIIt thiols are oxidized during the reduction of plasmin disulfides, establishing that AIIt directly participates in the reduction reaction. Incubation of HT1080 cells with plasminogen resulted in the rapid loss of thiol-specific labeling of AIIt by 3-(N-maleimidopropionyl)biocytin. The plasminogen-dependent oxidation of AIIt could be attenuated by thioredoxin. Thioredoxin reductase catalyzed the transfer of electrons from NADPH to the oxidized thioredoxin, thus completing the flow of electrons from NADPH to AIIt. Therefore, we identify AIIt as a substrate of the thioredoxin system and propose a new model for the role of AIIt in the redox-dependent processing of plasminogen and generation of an angiostatin at the cell surface.
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s100a10 annexin a2 and annexin a2 Heterotetramer as candidate plasminogen receptors
Frontiers in Bioscience, 2005Co-Authors: Mijung Kwon, Travis J Macleod, Yi Zhang, David M WaismanAbstract:Abstract The defining characteristic of a tumor cell is its ability to escape the constraints imposed by neighboring cells, invade the surrounding tissue and metastasize to distant sites. This invasive property of tumor cells is dependent on activation of proteinases at the cell surface. The serine proteinase plasmin is one of the key proteinases that participate in the pericellular proteolysis associated with the invasive program of tumor cells. The assembly of plasminogen and tissue plasminogen activator at the endothelial cell surface or on the fibrin clot provides a focal point for plasmin generation and therefore plays an important role in maintaining blood fluidity and promoting fibrinolysis. S100A10, a member of the S100 family of Ca2+-binding proteins, is a dimeric protein composed of two 11 kDa subunits. Typically, S100A10 is found in most cells bound to its annexin A2 ligand as the Heterotetrameric (S100A10)2(annexin A2)2 complex, AIIt. In addition to an intracellular distribution, S100A10 is present on the extracellular surface of many cells. The carboxyl-terminal lysines of S100A10 bind tPA and plasminogen resulting in the stimulation of tPA-dependent plasmin production. Carboxypeptidases cleave the carboxyl-terminal lysines of S100A10, resulting in a loss of binding and activity. Plasmin binds to S100A10 at a distinct site and the formation of the S100A10-plasmin complex stimulates plasmin autoproteolysis thereby providing a highly localized transient pulse of plasmin activity at the cell surface. The binding of tPA and plasmin to S100A10 also protects against inhibition by physiological inhibitors, PAI-1 and alpha2-antiplasmin, respectively. S100A10 also colocalizes plasminogen with the uPA-uPAR complex thereby localizing and stimulating uPA-dependent plasmin formation to the surface of cancer cells. The loss of S100A10 from the extracellular surface of cancer cells results in a significant loss in plasmin generation. In addition, S100A10 knock-down cells demonstrate a dramatic loss in extracellular matrix degradation and invasiveness as well as reduced metastasis. Annexin A2 plays an important role in plasminogen regulation by controlling the levels of extracellular S100A10 and by acting as a plasmin reductase. The mechanism by which annexin A2 regulates the extracellular levels of S100A10 is unknown. This review highlights the important part that S100A10 plays in plasmin regulation and the role this protein plays in cancer cell invasiveness and metastasis.
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the p11 subunit of annexin ii Heterotetramer is regulated by basic carboxypeptidase
Biochemistry, 2002Co-Authors: Darin K Fogg, Nolan R Filipenko, Kyusil Choi, Sandra L Fitzpatrick, Geetha Kassam, David E Bridges, Kitty Kit Ting Cheung, Michael E Nesheim, David M WaismanAbstract:The Ca 2 + -dependent phospholipid-binding protein annexin II Heterotetramer (AIIt) is composed of two copies of annexin II and a p1 I dimer. The interaction of the carboxyl-terminal lysine residues of the p1 1 subunit of AIIt with the lysine-binding kringle domains of plasminogen is believed to play a key role in plasminogen binding and stimulation of the tPA-catalyzed cleavage of plasminogen to plasmin. In the current report, we show that AIIt-stimulated plasminogen activation is regulated by basic carboxy-peptidases, in vitro. The incubation of AIIt with a 1/400 molar ratio of carboxypeptidase B for periods as short as 2 min resulted in a significant loss in AIIt-stimulated plasminogen activation. Carboxypeptidase B (CpB) as well as thrombin-activated fibrinolysis inhibitor (TAFIa) and carboxypeptidase N (CpN) rapidly reduced AIIt-stimulated plasminogen activation by 80%. The molar ratio of carboxypeptidase/AIIt for half-maximal inhibition of AIIt was 1/4700, 1/700, and 1/500 for CpB, TAFIa, and CpN, respectively. Treatment of AIIt with carboxypeptidase resulted in loss of both carboxyl-terminal lysine residues from the p1 1 subunit, which correlated with a decrease in the k c a t and an increase in the K m for plasminogen activation. The data reveal a novel mechanism for the regulation of AIIt-stimulated plasminogen activation.
Sergi Ferre - One of the best experts on this subject based on the ideXlab platform.
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Functional and Neuroprotective Role of Striatal Adenosine A2A Receptor Heterotetramers
Journal of caffeine and adenosine research, 2019Co-Authors: Sergi Ferre, Francisco CiruelaAbstract:In the striatum, adenosine A2A receptors (A2AR) are mainly expressed within the soma and dendrites of the striatopallidal neuron. A predominant proportion of these striatal postsynaptic A2AR form p...
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Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A2A-dopamine D2 receptor Heterotetramers and adenylyl cyclase
Frontiers in Pharmacology, 2018Co-Authors: Sergi Ferre, Jordi Bonaventura, Estefania Moreno, Candice Hatcher-solis, Jaume Taura, César Quiroz, Verònica Casadó-anguera, Alexxai V. KravitzAbstract:The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R Heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R Heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson’s disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons.
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allosteric mechanisms within the adenosine a2a dopamine d2 receptor Heterotetramer
Neuropharmacology, 2016Co-Authors: Sergi Ferre, Jordi Bonaventura, Dardo Tomasi, Gemma Navarro, Estefania Moreno, Antonio Cortes, Carme Lluis, Vicent Casado, Nora D VolkowAbstract:Abstract The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR)–dopamine D2 receptor (D2R) heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR–D2R heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs–Gi interaction within the frame of the heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’.
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the gpcr Heterotetramer challenging classical pharmacology
Trends in Pharmacological Sciences, 2015Co-Authors: Sergi FerreAbstract:Two concepts are gaining increasing acceptance in G protein-coupled receptor (GPCR) pharmacology: (i) pre-coupling of GPCRs with their preferred signaling molecules, and (ii) GPCR oligomerization. This is begging for the introduction of new models such as GPCR oligomer-containing signaling complexes with GPCR homodimers as functional building blocks. This model favors the formation of GPCR Heterotetramers – heteromers of homodimers coupled to their cognate G protein. The GPCR Heterotetramer offers an optimal framework for a canonical antagonistic interaction between activated Gs and Gi proteins, which can simultaneously bind to their respective preferred receptors and to adenylyl cyclase (AC) catalytic units. This review addresses the current evidence for pre-coupling of the various specific components that provide the very elaborate signaling machinery exemplified by the Gs–Gi–AC-coupled GPCR Heterotetramer.
Getu Beyene - One of the best experts on this subject based on the ideXlab platform.
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Cassava shrunken-2 homolog MeAPL3 determines storage root starch and dry matter content and modulates storage root postharvest physiological deterioration
Plant Molecular Biology, 2020Co-Authors: Getu Beyene, Raj Deepika Chauhan, Jackson Gehan, Dimuth Siritunga, Nigel TaylorAbstract:Key message Among the five cassava isoforms ( MeAPL1 – MeAPL5 ), MeAPL3 is responsible for determining storage root starch content. Degree of storage root postharvest physiological deterioration (PPD) is directly correlated with starch content. Abstract AGPase is Heterotetramer composed of two small and two large subunits each coded by small gene families in higher plants. Studies in cassava ( M anihot e sculenta ) identified and characterized five isoforms of M anihot e sculenta A DP-glucose p yrophosphorylase l arge subunit ( MeAPL1 – MeAPL5 ) and employed virus induced gene silencing (VIGS) to show that MeAPL3 is the key isoform responsible for starch and dry matter accumulation in cassava storage roots. Silencing of MeAPL3 in cassava through stable transgenic lines resulted in plants displaying significant reduction in storage root starch and dry matter content (DMC) and induced a distinct phenotype associated with increased petiole/stem angle, resulting in a droopy leaf phenotype. Plants with reduced starch and DMC also displayed significantly reduced or no postharvest physiological deterioration (PPD) compared to controls and lines with high DMC and starch content. This provides strong evidence for direct relationships between starch/dry matter content and its role in PPD and canopy architecture traits in cassava.
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Cassava shrunken-2 homolog MeAPL3 determines storage root starch and dry matter content and modulates storage root postharvest physiological deterioration
Plant Molecular Biology, 2020Co-Authors: Getu Beyene, Raj Deepika Chauhan, Jackson Gehan, Dimuth Siritunga, Nigel TaylorAbstract:Key message Among the five cassava isoforms ( MeAPL1 – MeAPL5 ), MeAPL3 is responsible for determining storage root starch content. Degree of storage root postharvest physiological deterioration (PPD) is directly correlated with starch content. Abstract AGPase is Heterotetramer composed of two small and two large subunits each coded by small gene families in higher plants. Studies in cassava ( M anihot e sculenta ) identified and characterized five isoforms of M anihot e sculenta A DP-glucose p yrophosphorylase l arge subunit ( MeAPL1 – MeAPL5 ) and employed virus induced gene silencing (VIGS) to show that MeAPL3 is the key isoform responsible for starch and dry matter accumulation in cassava storage roots. Silencing of MeAPL3 in cassava through stable transgenic lines resulted in plants displaying significant reduction in storage root starch and dry matter content (DMC) and induced a distinct phenotype associated with increased petiole/stem angle, resulting in a droopy leaf phenotype. Plants with reduced starch and DMC also displayed significantly reduced or no postharvest physiological deterioration (PPD) compared to controls and lines with high DMC and starch content. This provides strong evidence for direct relationships between starch/dry matter content and its role in PPD and canopy architecture traits in cassava.
Jordi Bonaventura - One of the best experts on this subject based on the ideXlab platform.
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Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A2A-dopamine D2 receptor Heterotetramers and adenylyl cyclase
Frontiers in Pharmacology, 2018Co-Authors: Sergi Ferre, Jordi Bonaventura, Estefania Moreno, Candice Hatcher-solis, Jaume Taura, César Quiroz, Verònica Casadó-anguera, Alexxai V. KravitzAbstract:The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R Heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R Heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson’s disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons.
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allosteric mechanisms within the adenosine a2a dopamine d2 receptor Heterotetramer
Neuropharmacology, 2016Co-Authors: Sergi Ferre, Jordi Bonaventura, Dardo Tomasi, Gemma Navarro, Estefania Moreno, Antonio Cortes, Carme Lluis, Vicent Casado, Nora D VolkowAbstract:Abstract The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR)–dopamine D2 receptor (D2R) heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR–D2R heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs–Gi interaction within the frame of the heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’.
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allosteric interactions between agonists and antagonists within the adenosine a2a receptor dopamine d2 receptor Heterotetramer
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Jordi Bonaventura, Gemma Navarro, Estefania Moreno, Veronica Casadoanguera, Karima Azdad, Marc Brugarolas, Josefa Mallol, Enric I Canela, Carme LluisAbstract:Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as Heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.