Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A-Dopamine D Receptor Heterotetramers and Adenylyl Cyclase
Ferré, Sergi (National Institutes of Health, Baltimore, United States)
Bonaventura, Jordi (National Institutes of Health, Baltimore, United States)
Zhu, Wendy (Circuit Therapeutics, Menlo Park, United States)
Hatcher-Solis, Candice (National Institutes of Health, Baltimore, United States)
Taura, Jaume (Universitat de Barcelona. Institut de Neurociències)
Quiroz, César (National Institutes of Health, Baltimore, United States)
Cai, Ning-Sheng (National Institutes of Health, Baltimore, United States)
Moreno, Estefanía (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Casadó-Anguera, Verònica (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Kravitz, Alexxai V. (National Institutes of Health, Bethesda, United States)
Thompson, Kimberly R. (Circuit Therapeutics, Inc., Menlo Park, United States)
Tomasi, Dardo G. (National Institutes of Health, Rockville, United States)
Navarro Brugal, Gemma (Universitat de Barcelona. Departament de Bioquímica i Fisiologia)
Cordomí Montoya, Arnau (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Lluís, Carme (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Dessauer, Carmen W. (University of Texas Health Science Center at Houston, United States)
Volkow, Nora D. (National Institutes of Health, Rockville, United States)
Casadó, Vicent (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Ciruela, Francisco (Universitat de Barcelona. Institut de Neurociències)
Logothetis, Diomedes E. (Northeastern University, Boston, United States)
Zwilling, Daniel (Circuit Therapeutics, Inc, Menlo Park, United States)

Fecha:	2018
Resumen:	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 D receptors (D2R) and adenosine A 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.
Ayudas:	Agencia Estatal de Investigación SAF2017-87349-R Ministerio de Economía y Competitividad SAF2014-54840-R Ministerio de Economía y Competitividad PIE14/00034
Nota:	Altres ajuts: Fundació La Marató de TV3 (20140610 and 20152031)
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Striatopallidal neuron ; Adenosine A receptor ; Dopamine D receptor ; GPCR heteromers ; Adenylyl cyclase ; Caffeine ; Akinesia ; Apathy
Publicado en:	Frontiers in Pharmacology, Vol. 9 (april 2018) , ISSN 1663-9812

DOI: 10.3389/fphar.2018.00243
PMID: 29686613

18 p, 1.7 MB

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