Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A<inf>2A</inf>-dopamine D<inf>2</inf> receptor heterotetramers and adenylyl cyclase

Sergi Ferré, Jordi Bonaventura, Wendy Zhu, Candice Hatcher-Solis, Jaume Taura, César Quiroz, Ning Sheng Cai, Estefanía Moreno, Verónica Casadó-Anguera, Alexxai V. Kravitz, Kimberly R. Thompson, Dardo G. Tomasi, Gemma Navarro, Arnau Cordomí, Leonardo Pardo, Carme Lluís, Carmen W. Dessauer, Nora D. Volkow, Vicent Casadó, Francisco CiruelaDiomedes E. Logothetis, Daniel Zwilling

Research output: Contribution to journalArticleResearchpeer-review

57 Citations (Scopus)


© 2018 Ferré, Bonaventura, Zhu, Hatcher-Solis, Taura, Quiroz, Cai, Moreno, Casadó-Anguera, Kravitz, Thompson, Tomasi, Navarro, Cordomí, Pardo, Lluís, Dessauer, Volkow, Casadó, Ciruela, Logothetis and Zwilling. 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.
Original languageEnglish
Article number243
JournalFrontiers in Pharmacology
Issue numberAPR
Publication statusPublished - 9 Apr 2018


  • Adenosine A receptor 2A
  • Adenylyl cyclase
  • Akinesia
  • Apathy
  • Caffeine
  • Dopamine D receptor 2
  • GPCR heteromers
  • Striatopallidal neuron


Dive into the research topics of 'Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A<inf>2A</inf>-dopamine D<inf>2</inf> receptor heterotetramers and adenylyl cyclase'. Together they form a unique fingerprint.

Cite this