Adenosine A1-Dopamine D1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron

Rivera-Oliver, Marla; Moreno, Estefanía; Álvarez-Bagnarol, Yocasta; Ayala-Santiago, Christian; Cruz-Reyes, Nicole; Molina‐Castro, Gian Carlo; Clemens, Stefan; Canela, Enric I.; Ferré, Sergi; Casadó, Vicent; Díaz‐Ríos, Manuel

doi:10.1007/s12035-018-1120-y

Cited by 33 publications

(31 citation statements)

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“…More generally, these results indicate that to inhibit a Gs-coupled receptor-mediated AC activation, the ligands need to simultaneously interact with heterotetramers of the corresponding Gs-coupled and Gi-coupled receptors. This has been so far shown for the A2AR-D2R [7], the A1R-D1R [48], the D1R-D3R [49], and now the A2AR-CB1R heterotetramers, where destabilization of their heteromeric interface leads to the disruption of the canonical Gs-Gi antagonistic interaction at the AC level without disruption of the Gi-coupled receptor-mediated inhibition of forskolin-induced AC activation.…”

Section: Discussionmentioning

confidence: 64%

Control of glutamate release by complexes of adenosine and cannabinoid receptors

et al. 2020

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Background: It has been hypothesized that heteromers of adenosine A 2A receptors (A2AR) and cannabinoid CB 1 receptors (CB1R) localized in glutamatergic nerve terminals mediate the integration of adenosine and endocannabinoid signaling involved in the modulation of striatal excitatory neurotransmission. Previous studies have demonstrated the existence of A2AR-CB1R heteromers in artificial cell systems. A dependence of A2AR signaling for the Gi protein-mediated CB1R signaling was described as one of its main biochemical characteristics. However, recent studies have questioned the localization of functionally significant A2AR-CB1R heteromers in striatal glutamatergic terminals. Results: Using a peptide-interfering approach combined with biophysical and biochemical techniques in mammalian transfected cells and computational modeling, we could establish a tetrameric quaternary structure of the A2AR-CB1R heterotetramer. This quaternary structure was different to the also tetrameric structure of heteromers of A2AR with adenosine A 1 receptors or dopamine D 2 receptors, with different heteromeric or homomeric interfaces. The specific quaternary structure of the A2A-CB1R, which depended on intermolecular interactions involving the long C-terminus of the A2AR, determined a significant A2AR and Gs protein-mediated constitutive activation of adenylyl cyclase. Using heteromer-interfering peptides in experiments with striatal glutamatergic terminals, we could then demonstrate the presence of functionally significant A2AR-CB1R heteromers with the same biochemical characteristics of those studied in mammalian transfected cells. First, either an A2AR agonist or an A2AR antagonist allosterically counteracted Gimediated CB1R agonist-induced inhibition of depolarization-induced glutamate release. Second, co-application of both an A2AR agonist and an antagonist cancelled each other effects. Finally, a CB1R agonist inhibited glutamate release dependent on a constitutive activation of A2AR by a canonical Gs-Gi antagonistic interaction at the adenylyl cyclase level.

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Section: Discussionmentioning

confidence: 64%

Control of glutamate release by complexes of adenosine and cannabinoid receptors

et al. 2020

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“…Adenosine acts at A1 receptors to inhibit interneurons within the CPG, which in turn affects the frequency of motor output. Previous research has focussed on the astrocyte-to-neuron communication mechanisms that may impact motor circuits (Witts et al, 2012(Witts et al, , 2015Miles, 2015, 2017;Acevedo et al, 2016;Acton et al, 2018;Rivera-Oliver et al, 2018). In this study, we have identified previously unexplored neuron-to-astrocyte signaling mechanisms which may drive astrocyte-dependent modulation of the spinal cord locomotor CPG.…”

Section: Discussionmentioning

confidence: 92%

“…There is converging evidence that stimulating astrocytes pharmacologically, or ablating astrocytes with gliotoxins, reveals purinergic-dependent, glial-derived modulation of the spinal cord locomotor CPG (Dale and Gilday, 1996;Dale, 1998;Brown and Dale, 2000;Witts et al, 2012Witts et al, , 2015Acton and Miles, 2015;Acevedo et al, 2016;Acton and Miles, 2017;Acton et al, 2018;Rivera-Oliver et al, 2018). Although astrocytes in other CNS regions demonstrate the ability to utilize other transmitters, such as glutamate or GABA (Malarkey and Parpura, 2008;Christensen et al, 2018); there is a paucity of evidence to suggest that other gliotransmitters are involved in the astrocytic control of the locomotor CPG.…”

Section: Discussionmentioning

confidence: 99%

“…Our data, therefore, support previously proposed mechanisms of glial-mediated modulation of the spinal locomotor CPG. The theory stands that astrocytes release ATP, which is subsequently converted to adenosine, which then acts at heteromeric dimers comprised of A1 adenosine and D1 dopaminergic receptors on CPG interneurons to reduce neuronal activity (Witts et al, 2015;Acton and Miles, 2017;Acton et al, 2018;Rivera-Oliver et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

Broadhead

Miles

2020

Front. Cell. Neurosci.

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Evidence suggests that astrocytes are not merely supportive cells in the nervous system but may actively participate in the control of neural circuits underlying cognition and behavior. In this study, we examined the role of astrocytes within the motor circuitry of the mammalian spinal cord. Pharmacogenetic manipulation of astrocytic activity in isolated spinal cord preparations obtained from neonatal mice revealed astrocytederived, adenosinergic modulation of the frequency of rhythmic output generated by the locomotor central pattern generator (CPG) network. Live Ca 2+ imaging demonstrated increased activity in astrocytes during locomotor-related output and in response to the direct stimulation of spinal neurons. Finally, astrocytes were found to respond to neuronally-derived glutamate in a metabotropic glutamate receptor 5 (mGluR5) dependent manner, which in turn drives astrocytic modulation of the locomotor network. Our work identifies bi-directional signaling mechanisms between neurons and astrocytes underlying modulatory feedback control of motor circuits, which may act to constrain network output within optimal ranges for movement. LAY SUMMARYWe have investigated how astrocytes, a type of supportive cell within the nervous system, may be directly involved in the control of movements, such as walking (locomotion). We found that astrocytes are active participants in the neural circuits of the mammalian spinal cord that control locomotion. The function of astrocytes within these networks appears to relate to the modulation of locomotor speed. We also identify the chemical signaling pathways involved in a modulatory feedback loop between astrocytes and neurons. Our findings suggest that this bi-directional communication between astrocytes and neurons may act to constrain spinal motor circuits within operational ranges for desired movements.

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“…However, changes to A 1 R and A 2A R expression following exercise could have a particularly potent influence on striatal function through its modulation of dopaminergic activity. Indeed, A 1 Rs and A 2A Rs form heteromeric complexes with dopamine 1 (D 1 R) with dopamine 2 (D 2 R) receptors, respectively [24,[36][37][38][39][40]. Agonist binding at A 1 Rs and A 2A Rs results in conformational changes to dopamine receptors and decreases dopamine receptor coupling to G-proteins, thereby reducing the effectiveness of dopaminergic signaling within the striatum [39][40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

Exercise-Induced Adaptations to the Mouse Striatal Adenosine System

2020

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Adenosine acts as a key regulator of striatum activity, in part, through the antagonistic modulation of dopamine activity. Exercise can increase adenosine activity in the brain, which may impair dopaminergic functions in the striatum. Therefore, long-term repeated bouts of exercise may subsequently generate plasticity in striatal adenosine systems in a manner that promotes dopaminergic activity. This study investigated the effects of long-term voluntary wheel running on adenosine 1 (A1R), adenosine 2A (A2AR), dopamine 1 (D1R), and dopamine 2 (D2R) receptor protein expression in adult mouse dorsal and ventral striatum structures using immunohistochemistry. In addition, equilibrative nucleoside transporter 1 (ENT1) protein expression was examined after wheel running, as ENT1 regulates the bidirectional flux of adenosine between intra- and extracellular space. The results suggest that eight weeks of running wheel access spared age-related increases of A1R and A2AR protein concentrations across the dorsal and ventral striatal structures. Wheel running mildly reduced ENT1 protein levels in ventral striatum subregions. Moreover, wheel running mildly increased D2R protein density within striatal subregions in the dorsal medial striatum, nucleus accumbens core, and the nucleus accumbens shell. However, D1R protein expression in the striatum was unchanged by wheel running. These data suggest that exercise promotes adaptations to striatal adenosine systems. Exercise-reduced A1R and A2AR and exercise-increased D2R protein levels may contribute to improved dopaminergic signaling in the striatum. These findings may have implications for cognitive and behavioral processes, as well as motor and psychiatric diseases that involve the striatum.

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Adenosine A1-Dopamine D1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron

Cited by 33 publications

References 70 publications

Control of glutamate release by complexes of adenosine and cannabinoid receptors

Control of glutamate release by complexes of adenosine and cannabinoid receptors

Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

Exercise-Induced Adaptations to the Mouse Striatal Adenosine System

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