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. Author manuscript; available in PMC: 2009 Jan 1.
Published in final edited form as: Curr Pharm Des. 2008;14(15):1468–1474. doi: 10.2174/138161208784480108

An Update on Adenosine A2A-Dopamine D2 receptor interactions. Implications for the Function of G Protein-Coupled Receptors

S Ferré 1,*, C Quiroz 1, A S Woods 1, R Cunha 2, P Popoli 3, F Ciruela 4, C Lluis 5, R Franco 5, K Azdad 6, S N Schiffmann 6
PMCID: PMC2424285  NIHMSID: NIHMS51867  PMID: 18537670

Abstract

Adenosine A2A-dopamine D2 receptor interactions play a very important role in striatal function. A2A-D2 receptor interactions provide an example of the capabilities of information processing by just two different G protein-coupled receptors. Thus, there is evidence for the coexistence of two reciprocal antagonistic interactions between A2A and D2 receptors in the same neurons, the GABAergic enkephalinergic nens. An antagonistic A2A-D2 intramembrane receptor interaction, which depends on A2A-D2 receptor heteromerization and Gq/11-PLC signaling, modulates neuronal excitability and neurotransmitter release. On the other hand, an antagonistic A2A-D2 receptor interaction at the adenylyl-cyclase level, which depends on Gs/olf- and Gi/o- type V adenylyl-cyclase signaling, modulates protein phosphorylation and gene expression. Finally, under conditions of upregulation of an activator of G protein signaling (AGS3), such as during chronic treatment with addictive drugs, a synergistic A2A-D2 receptor interaction can also be demonstrated. AGS3 facilitates a synergistic interaction between Gs/olf- and Gi/o- coupled receptors on the activation of types II/IV adenylyl cyclase, leading to a paradoxical increase in protein phosphorylation and gene expression upon co-activation of A2A and D2 receptors. The analysis of A2-D2 receptor interactions will have implications for the pathophysiology and treatment of basal ganglia disorders and drug addiction.

Keywords: Adenosine A2A Receptor, Dopamine D2 Receptor, G Protein-Coupled Receptors, Receptor Heteromers, Striatum, Basal Ganglia Disorders, Drug Addiction

LOCALIZATION OF THE A2A-D2 RECEPTOR HETEROMER

Applying a broad definition of “neurotransmitter” [1], adenosine can be considered as an important neurotransmitter in the CNS, which acts through different subtypes of G protein-coupled receptors (GPCRs). From the four cloned adenosine receptors (adenosine A1, A2A, A2B and A3 receptors), A1 and A2A receptors are the main targets for the physiological effects of adenosine in the brain [2]. A1 receptor is widely distributed in the brain, including the striatum, while A2A receptor is mostly concentrated in the striatum [2,3]. It is becoming increasingly obvious that the modulatory role of adenosine in the striatum is related to the ability of A1 and A2A receptors to heteromerize with themselves and with other GPCRs, such as dopamine, glutamate, cannabinoid and ATP receptors [4-14]. The present review focuses on the role of one particular adenosine receptor heteromer, the one constituted by the A2A and the dopamine D2 receptor, which is already having important implications for the treatment of neuropathologies involving the striatum (see below).

Striatal medium spiny neurons are GABAergic efferent neurons which constitute more that 95% of the striatal neuronal population. They receive two main afferents, cortical-limbic-thalamic glutamatergic inputs and dopaminergic mesencephalic inputs, from the substantia nigra pars compacta and the VTA. These inputs converge in the dendritic spine, with the glutamatergic input making synaptic contact with the head of the dendritic spine and the dopaminergic input making synaptic contact with the neck of the dendritic spine [15,16]. The dendritic spine, the glutamatergic terminal, the dopaminergic terminal and astroglial processes that wrap the glutamatergic synapse constitute the most common local module in the striatum, which we have recently called striatal spine module [16]. In the striatal spine module adenosine plays a very important role in the modulation of both glutamatergic and dopaminergic neurotransmission [14,16,17].

It was initially thought that most extracellular adenosine came from intracellular adenosine as a product of ATP, due to an increased metabolic demand of the cell [17]. However, recent studies suggest that astroglia plays a very important role in the production of extracellular adenosine. Astrocytes express glutamate and ATP receptors, which when activated induce astrocytes to release glutamate and ATP, which can then be converted to adenosine by means of ectonucleotidases [18-20]. This adds more relevance to the already known key role of astrocytes in the computation of information in the striatal spine module [16,18,19]. Finally, increasing evidence suggests that ATP is co-released with glutamate by the glutamatergic terminals and converted to adenosine by ectonucleotidases [14,16].

There are two subtypes of GABAergic striatal efferent neurons, the GABAergic striopallidal neuron, which can be called GABAergic enkephalinergic neuron, since it expresses the peptide enkephalin, and the GABAergic striatonigral-striatoentopeduncular neuron, which can be called GABAergic dynorphynergic neuron, since it expresses the peptide dynorphin (and also substance P). The GABAergic enkephalinergic neuron predominantly expresses dopamine and adenosine receptors of the D2 and A2A receptor subtype [3,9,14-17,21-23], while the GABAergic dynophynergic neuron expresses dopamine and adenosine receptors of the D1 and A1 subtype [3,9,23].

We found evidence for the existence of A2A-D2 receptor interactions that modulate the function of the GABAergic enkephalinergic neuron and A1-D1 receptor interactions that modulate the function of GABAergic dynorphinergic neuron [23]. We and other authors also found evidence for the existence of selective heteromerization of A2A and D2 receptors and A1 and D1 receptors in transfected cells [4,8,10,11] and found biochemical characteristics of these receptor heteromers, called “intramembrane receptor-receptor interactions” [9], which could also be identified in the striatum (reviewed in ref. 22), therefore demonstrating the existence of A2A-D2 and A1-D1 receptor heteromers in the brain [14,24,25].

Then, going back to the striatal spine module, we have to differentiate between two types of modules, the one centered at the dendritic spine of the GABAergic enkephalinergic neuron, which contains A2A-D2 receptor heteromers, and the one centered at the dendritic spine of the dynorphinergic neuron, which contains A1-D1 receptor heteromers. In addition to the A2A-D2 and A1-D1 receptor heteromers, we have identified A1-A2A receptor heteromers in the glutamatergic terminals of, most probably, both striatal spine modules [12]. Furthermore, there is functional evidence for the existence of presynaptic interactions between A2A and D2 (or maybe D4) receptors that modulate striatal glutamate release (see below).

THE ANTAGONISTIC A2A-D2 INTRAMEMBRANE RECEPTOR INTERACTION

A2A-D2 receptor heteromerization was first demonstrated in mammalian transfected cells with co-immunoprecipitation, and fluorescence and bioluminescence resonance energy transfer techniques (FRET and BRET, respectively) [10,11] (Fig. 1). By using computerized modeling, pull-down and mass spectrometry techniques, it was shown that this heteromerization depends on an electrostatic interaction between an arginine-rich epitope of the N-terminal segment of the third intracellular loop (NI3L) of the D2 receptor and a phosphate group in the C-terminus of the A2A receptor [10,26,27]. FRET and BRET, however, are difficult techniques to implement in tissues and the demonstration of the A2A-D2 receptor heteromer was demonstrated by indirect means, by identifying a biochemical characteristic, what we have called a “biochemical fingerprint” of the heteromer [14,24,25].

Figure 1.

Figure 1

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Bioluminiscence and fluorescence resonance energy transfer (BRET and FRET, respectively) techniques allow the demonstration of neurotransmitter receptor heteromers in the natural environment of the living cell. FRET can be obtained when two fluorescent proteins, one acting as a donor and the other acting as acceptor, are close enough (within 10 nm). Therefore, to demonstrate receptor dimerization, cDNA constructs of one receptor fused to the fluorescent donor and another receptor fused to the fluorescent acceptor are prepared and transfected in a heterologous cell system. Different versions of the green fluorescent protein (GFP) are currently used as donors whereas yellow fluorescent proteins (YFPs) are used as acceptors. If the two receptors are forming dimers, the acceptor fluorescent signal is detected after donor excitation. In BRET, instead of a fluorescent donor one of the receptors is fused to the luminescent protein, Renilla luciferase (Rluc), which upon addition of a substrate (coelenterazine or Deep Blue C) allows energy transfer and excitation of the fluorescent acceptor.

The concept of “intramembrane receptor interactions” was first described by Luigi Agnati and Kjell Fuxe more than 20 years ago (reviewed in ref. 9). In these interactions, stimulation of one receptor changes the binding characteristics of an adjacent receptor in membrane preparations from brain tissue or transfected cells. It is now recognized that intramembrane receptor interactions constitute a common biochemical characteristic of receptor heteromers [14,23-25]. The antagonistic A2A-D2 intramembrane receptor interaction has been repeatedly reported by different research groups in membrane preparations from different transfected cell lines and from human and rat striatum [28-34]. In these membrane preparations, the addition of a selective A2A receptor agonist decreases the ability of dopamine (or a D2 receptor agonist) to displace the binding of a selective D2 receptor radioligand [28-34] (Fig. 2a).

Figure 2.

Figure 2

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Different types of A2A-D2 receptor interactions: a. antagonistic A2A-D2 intramembrane receptor interaction which depends on A2A-D2 receptor heteromerization and Gq/11-PLC signaling; b. antagonistic A2A-D2 receptor interaction at the adenylyl-cyclase level, which depends on Gs/olf- and Gi- type V adenylyl-cyclase signaling; c. synergistic A2A-D2 receptor interaction at the adenylyl-cyclase level, which depends on upregulation of AGS3 and Gs/olf- and Gi- type II/IV adenylyl-cyclase signaling.

The antagonistic A2A-D2 intramembrane receptor interaction seems to determine the ability of A2A receptors to control the inhibitory role of D2 receptors on neuronal excitability and neurotransmitter release in the GABAergic enkephalinergic neuron. It was demonstrated by means of in vivo microdialysis experiments that the perfusion of a D2 receptor agonist in the dorsal striatum, localization of the cell bodies of the GABAergic enkephalinergic neuron, leads to a decrease in the extracellular levels of GABA in the ipsilateral globus pallidus, localization of the nerve terminals of the enkephalinergic neurons [35]. On the other hand, the striatal perfusion of an A2A receptor agonist did not produce any significant effect, but it completely counteracted the effect of the D2 receptor agonist [35]. Thus, in this experimental setting, an A2A receptor agonist behaves as a D2 receptor antagonist. In the nucleus accumbens (ventral striatum), there is a more tonic effect of D2 receptor stimulation by endogenous dopamine on neurotransmitter release by the GABAergic enkephalinergic neuron [36]. Also in this experimental setting the striatal perfusion of an A2A receptor agonist produced the same effects than a D2 receptor antagonist, i.e., an increase in the extracellular levels of GABA in the ipsilateral ventral pallidum [36].

The striatal output is determined by the bursting activity of the GABAergic striatal efferent neurons. These bursts are driven by cortico-striatal inputs that depolarize the GABAergic enkephalinergic and dynorphinergic neurons from their resting hyperpolarized membrane potential around -80 mV, the down-state, to a more depolarized level near -55 mV, the up-state [37]. These down- to up-state transitions require channels that can be regulated by striatal transmitters acting through GPCRs, such as the interacting A2A and D2 receptors in the GABAergic enkephalinergic neurons. In a recent study, perforated patch clamp recordings on acute brain slices, together with the loading of competitive peptides to block specific protein-protein interactions, were used to characterize the role of A2A-D2 receptors interactions in the modulation of down- to up-state transitions, modeled in vitro by the application of NMDA. A D2 receptor agonist abolished the firing in up-state and inhibited the down/up-state transition in the GABAergic enkephalinergic neurons by a mechanism involving the regulation of L-type calcium channel CaV1.3 through protein-protein interactions with scaffold proteins Shank1/3 (Azdad et al., Society for Neuroscience Abstracts, 2007). On the other hand, the A2A receptor agonist CGS 21680 did not induce any modification in state transition or in the firing frequency, but it totally reversed the effects of D2 receptor activation (Azdad et al.). This action was blocked by the selective A2A receptor antagonist SCH 58261 (1μM) and was absent in A2A receptor knock-out mice (Azdad et al.). The application of peptides containing the same aminoacid sequence than the epitopes involved in A2A-D2 receptor heteromerization counteracted the ability of A2A receptor activation to antagonize the effect of D2 receptor activation (Azdad et al.). This demonstrates that A2A-D2 receptors heteromerization is strictly mandatory for the A2A receptor-mediated control of D2 receptor-mediated modulation of the excitability of GABAergic enkephalinergic neurons.

These effects on neurotransmitter release and neuronal excitability are paralleled by effects on motor activity and other behavioral responses, where selective A2A receptor agonists or antagonists respectively counteract or potentiate the motor activation induced by dopamine D2 receptor agonists [38-42]. Consequently, we predicted 15 years ago that A2A receptor antagonists could be useful in Parkinson’s disease, especially potentiating the effects of L-dopa or D2 receptor agonists [43]. In fact, in different experimental models of Parkinson’s disease, A2A receptor antagonists potentiate the motor activating effects of L-DOPA or D2 receptor agonists (for review see ref. 42). Also in agreement, in the rodent dopamine-denervated striatum, local application of a D2 receptor agonist potently inhibits the increased neuronal activity (compared with the non-denervated striatum) and this effect is counteracted or potentiated with application of A2A agonists or antagonists, respectively [41]. Importantly, the A2A receptor ligands did not have any significant effects on their own [41]. On the other hand, in patients with Parkinson’s disease the association of L-DOPA and an A2A receptor antagonist has already given promising therapeutic results (reviewed in ref. 44).

THE ANTAGONISTIC A2A-D2 RECEPTOR INTERACTION AT THE SECOND MESSENGER LEVEL

A2A receptor, through its coupling to Golf proteins, can potentially stimulate adenylyl-cyclase and activate the cAMP-PKA signaling pathway, with phosphorylation of several PKA substrates, such as DARPP-32, CREB and AMPA receptors and the consequent increase in the expression of different genes, such as c-fos or preproenkephalin in the GABAergic enkephalinergic neuron [3,9,14,16,23,24]. For instance, in CHO cells stably transfected with A2A receptors, the addition of an A2A receptor agonist produced cAMP accumulation, CREB phosphorylation and increase in c-fos expression [31]. In the same cell line we could demonstrate the existence of an antagonistic A2A-D2 intramembrane receptor interaction with radioligand binding experiments [31]. Furthermore, in the same cell line, we found a reciprocal antagonistic A2A-D2 receptor interaction by which the D2 receptor, which can couple to Gi/o proteins, inhibits the effects of A2A receptor stimulation at the level of adenylyl cyclase [31] (Fig. 2b). A D2 receptor agonist did not produce a significant effect on its own, but it completely counteracted the effect induced by A2A receptor stimulation on cAMP accumulation, CREB phosphorylation and c-fos expression [31].

The two kind of reciprocal antagonistic A2A-D2 receptor interactions could also be demonstrated in another cell line, a human SH-SY5Y neuroblastoma cell line that constitutively expresses A2A receptors and with transfected D2 receptors [32]. In this cell line, D2 receptor stimulation completely counteracted cAMP accumulation induced by an A2A receptor agonist [8]. But, at the same time, an antagonistic A2A-D2 intramembrane receptor interaction with functional consequences could be demonstrated with radioligand binding experiments and intracellular Ca2+responses. Thus, D2 receptor activation inhibited a KCL-induced increase in intracellular concentration of Ca2+, which was counteracted by A2A receptor stimulation [32]. This is most probably the same mechanism by which the antagonistic A2A-D2 intramembrane receptor interaction controls the excitability of the GABAergic enkephalinergic neurons (see above).

It is intriguing that both types of reciprocal antagonistic A2A-D2 receptor interactions coexist in the same cells and, in fact, they do coexist in the brain. Under normal conditions, there is a strong tonic activation of D2 receptors that blocks the ability of A2A receptors to signal through the cAMP-PKA pathway. For instance, in the rodent striatum, the in vivo administration of D2 receptor antagonists produces a significant increase in the PKA-dependent phosphorylation of DARPP-32 or the AMPA receptor and an increase in the expression of c-fos and preproenkephalin genes, which depends on the ability of D2 receptor blockade to liberate A2A receptor signaling activated by endogenous adenosine [45,46]. Thus, the effect of the D2 receptor antagonists was counteracted by the previous administration of an A2A receptor antagonist, which did not have a significant effect on its own [45,46].

COEXISTENCE OF THE RECIPROCAL ANTAGONISTIC A2A-D2 RECEPTOR INTERACTIOSN

There is therefore evidence for the coexistence of two reciprocal antagonistic interactions between A2A and D2 receptors in the GABAergic enkephalinergic neurons. There is an antagonistic A2A-D2 intramembrane receptor interaction, which depends on A2A-D2 receptor heteromerization, which modulates neuronal excitability and neurotransmitter release; and there is an antagonistic A2A-D2 receptor interaction at the level of adenylyl-cyclase that modulates protein phosphorylation and gene expression. These results provide a clear example of a functional dissociation between neuronal excitability and gene expression. Thus, co-stimulation of A2A and D2 receptors implies a simultaneous A2A receptor-mediated inhibition of the D2 receptor-mediated modulation of neuronal excitability and a D2 receptor-mediated inhibition of the A2A receptor-mediated modulation of gene expression.

There are at least two possible, but not exclusive, mechanisms that could explain this apparently incompatible coexistence of reciprocal antagonistic A2A-D2 receptor interactions. First, one possibility is a different G-protein coupling between different sets of D2 receptors. Thus, it has been shown that D2 receptor couples to Gi/o, and therefore negatively to adenylyl-cyclase, when not forming heteromers, and that it couples to Gq/11-PLC signaling when forming heteromers with D1 receptors [47]. In fact, A2A receptor is morphologically and functionally very similar to the D1 receptor. They both have a short third intracellular loop and a long acidic C-terminus and they both couple to Golf proteins in the striatum. Also, they most probably use the same epitope (phosphorylated serine in the C-terminus) for their physical interaction with the D2 receptor [27]. Furthermore, the inhibitory role of D2 receptors in the excitability of GABAergic enkephalinergic neurons depends mostly on the suppression of Ca2+currents through L-type voltage-dependent calcium channels, which depends on activation of the Gq/11-PLC signaling pathway [37].

As shown in Fig. 2, the most probable scenario is the one that considers that, when not forming heteromers, the most common basic composition of A2A and D2 receptors and any GPCR is as homodimers [25,48-52], and that only one (heterotrimeric) G protein binds to a receptor dimer [48-50]. The selectivity of G protein recognition is determined by multiple intracellular regions, with the most critical regions being the second intracellular loop (I2L), the NI3L and the C-terminal segment of the third intracellular loop [53]. The relative contribution of these intracellular receptor domains to the selectivity of G protein recognition varies among different clases of GPCRs [53]. For D2 receptors, the arginine-rich epitope of the NI3L has been shown to be fundamental for the coupling to Gi/o proteins [54]. The same epitope has been demonstrated to bind to calmodulin and, as mentioned before, to the C-terminus of the A2A receptor [10,26,27,55,56]. These findings would agree with the inability of D2 receptor heteromers to signal through Gi/o proteins when bound to A2A receptors (see above) or to calmodulin [55].

Another possibility for the coexistence of reciprocal antagonistic A2A-D2 receptor interactions is the existence of an additional partner for A2A and D2 receptors to interact at the adenylyl-cyclase level. A2A receptors have also been found to form receptor heteromers with metabotropic glutamate mGlu5 receptors both in transfected cells and in the striatum [7]. In transfected cells and in the striatum, co-stimulation of A2A and mGlu5 receptors produced a very synergistic effect on c-fos expression, which depends on interactions between both receptors at the adenyl-cyclase and at the MAPK levels [7,57]. In vivo experiments demonstrated that co-stimulation of A2A and mGlu5 receptors, with the central administration of selective agonists, allows A2A receptor to get rid of the tonic inhibitory effect of D2 receptor and signal through cAMP-PKA pathway [7]. Since these A2A-mGlu5-D2 receptor interactions can be demonstrated in animal models of Parkinson’s disease [58,59], we postulated that co-administration of A2A and mGlu5 receptor antagonists could be used as a therapeutic strategy in this disease [58]. Similarly, in vivo microdialysis experiments have shown that A2A-mGlu5-D2 receptor interactions modulate the function of the GABAergic enkephalinergic neurons of the nucleus accumbens [60], which can have implications for schizophrenia and drug addiction.

THE SYNERGISTIC A2A-D2 RECEPTOR INTERACTION AT THE G PROTEIN LEVEL

The antagonistic A2A-D2 receptor interaction at the adenylyl cyclase level just described depends on the ability of activated D2 receptors to counteract A2A receptor-mediated type V adenylyl-cyclase (ACV) activation [61]. Under some conditions, a synergistic A2A-D2 receptor interaction can also be detected [34,62], which seems to depend on the presence of an activator of G protein signaling (AGS3), which facilitates a synergistic interaction between Gs/olf- and Gi/o-coupled receptors on the activation of types II/IV adenylyl cyclase (ACII/IV) (reviewed in ref. 63). AGS3 binds preferentially to Giα, and stabilizes the GDP-bound conformation of Gi, thereby dampening the signaling of the receptor through Gi-GTP, while simultaneously increasing the activity of Gβγ-regulated effectors [64]. Upon co-activation of the Gi-coupled D2 receptor, unbound βγ subunits released in the presence of AGS3 are free to transiently stimulate ACII/IV upon co-activation of the Golf-coupled A2A receptor, leading to a paradoxical increase in cAMP-PKA signaling [63] (Fig. 2c).

The antagonistic A2A-D2 receptor interaction at the adenylyl-cyclase is however predominant in most conditions, since ACV is the most expressed type of adenylyl-cyclase in the striatum [65]. However, the synergistic interaction can become particularly important during conditions of upregulation of AGS3, such as during chronic treatment with addictive drugs. It has recently been shown that withdrawal from repeated treatment with cocaine (self- or non-self-administered) up-regulates AGS3 in the prefrontal cortex and in the core region of the nucleus accumbens [66]. In rats, knocking down AGS3 expression in the prefrontal cortex or the nucleus accumbens core (with antisense oligonucleotides) counteracts reinstatement of cocaine- or heroin-seeking behaviour, respectively [66,67]. Therefore, upregulation of AGS3, with the consequent dampening of Giα signaling while simultaneously promoting βγ-dependent signaling of Gs-coupled receptors, such as D1 in the prefrontal cortex or in the nucleus accumbens [66], or A2A in the nucleus accumbens [63], can be an important mechanism responsible for the pathophysiologic changes associated with different addictive drugs. Thus, we have postulated that A2A receptor antagonists could be useful in the treatment of drug addiction and relapse during drug withdrawal [63].

PRESYNAPTIC ANTAGONISTIC A2A-D2 RECEPTOR INTERACTIONS

The GABAergic enkephalinergic neuron does not only express A2A and D2 receptors in the somatodendritic area, but both receptors are also colocalized in the nerve terminals [16]. Stimulation of A2A receptors in the globus pallidus, localization of the nerve terminals of the GABAergic enkephalinergic neurons, has been shown to stimulate GABA release by using in vivo microdialysis and slice preparations [68-70]. This effect of A2A receptor stimulation is dependent on the activation of the cAMP-PKA pathway [70], which depends on the already reported ability of PKA to phosphorylate different elements of the machinery involved in vesicular fusion [71]. In fact, the ability of A2A receptors to stimulate neurotransmitter release through cAMP-PKA signaling has also been demonstrated for acetylcholine in the striatum [72] and serotonin in the hippocampus [73]. In the globus pallidus, stimulation of D2 receptors produces a strong counteraction of A2A receptor-mediated GABA release [68,70]. Altogether, this has all the characteristics of the antagonistic A2A-D2 receptor interaction at the second messenger level described above, which does not seem to depend on A2A-D2 receptor heteromerization. Recent studies in an animal model of Parkinson’s disease suggest that this pallidal A2A-D2 receptor interaction may contribute to the antiparkinsonian effects of the coadministration of A2A antagonists and L-DOPA or D2 receptor agonists [74].

Finally, there is still another presynaptic localization where A2A-D2 receptor interactions seem to have an important functional role. We have recently demonstrated that A2A receptors localized in striatal glutamatergic terminals play a very important control of striatal glutamate release [12]. These receptors form heteromers with A1 receptors, and the A1-A2A receptor heteromer constitutes a “concentration-dependent switch” that regulates glutamate release depending on the extracellular concentration of adenosine. Thus, low concentrations of adenosine inhibit glutamate release by stimulating the A1 receptor, while higher concentrations induce glutamate release by also stimulating A2A receptors, which shuts down A1 receptor signaling by means of an antagonistic A1-A2A intramembrane receptor interaction [3,12,14,16,17]. However, the A2A receptor-dependent modulation of glutamate release seems to be under an inhibitory control by a co-localized D2 receptor. Thus, dopamine denervation strongly potentiates A2A receptor agonist-mediated stimulation of striatal glutamate release [71]. Again, this has the biochemical characteristics of an antagonistic A2A-D2 receptor interaction at the second messenger level, which might not depend on A2A-D2 receptor heteromerization or which might depend on A2A-mGlu5-D2 receptor interactions (see above). In fact, A2A and mGlu5 receptors have been found to be co-localized in a large proportion of striatal glutamatergic terminals, where they facilitate glutamate release in a synergistic manner [76]. This presynaptic antagonistic A2A-D2 receptor interaction can also have implications for the treatment of Parkinson’s disease with the co-administration of A2A antagonists and L-DOPA or D2 receptor agonists. Thus, in the striatum of parkinsonian animals there is overactivity of striatal glutamatergic transmission, which is restored with L-DOPA treatment. In recent electrophysiological experiments in cortico-striatal slices, concomitant activation of D2 receptors and inactivation of A2A receptors has shown to produce a very significant decrease in striatal glutamate release [77].

CONCLUSIONS

In conclusion, we are beginning to understand the complexities of A2-D2 receptor interactions, which play a very important role in basal ganglia physiology. Furthermore, it is obvious that the analysis of the different A2A-D2 receptor interactions will have important general implications about the processing of information of GPCRs. The present review stresses the fact that multiple and functionally different interactions can occur between just two different GPCRs, sometimes involving receptor heteromerization. Particularly important is the example of the coexistence of two apparently incompatible reciprocal antagonistic interactions between A2Aand D2 receptors, which allows a segregated control of neuronal excitability and gene expression in the GABAergic enkephalinergic neurons by the same receptors. The analysis of A2-D2 receptor interactions will also have implications for the pathophysiology and treatment of basal ganglia disorders and drug addiction, in view of their key processing role in the computation of information by the striatal spine module [16].

ACKNOWLEDGEMENTS

Supported by the NIDA IRP funds and grants from FRS-FNRS and FMRE (to SNS), Spanish “Ministerio de Educación y Ciencia” (SAF2005-00903 to FC), “Ministerio de Ciencia y Tecnología” (SAF2006-05481) and “Fundació La Marató TV3 (060110).

REFERENCES

  • [1].Snyder SH, Ferris CD. Novel neurotransmitters and their neuropsychiatric relevance. Am J Psychiatry. 2000;157:1738–51. doi: 10.1176/appi.ajp.157.11.1738. [DOI] [PubMed] [Google Scholar]
  • [2].Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001;53:527–52. [PMC free article] [PubMed] [Google Scholar]
  • [3].Schiffmann SN, Fisone G, Moresco R, Cunha R, Ferré S. Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol. 2007;83:277–92. doi: 10.1016/j.pneurobio.2007.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Ginés S, Hillion J, Torvinen M, Le Crom S, Casado V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Verniera P, Lluis C, Ferré S, Fuxe K, Franco R. Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci. USA. 2000;97:8606–11. doi: 10.1073/pnas.150241097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Ciruela F, Escriche M, Burgueno J, Angulo E, Casado V, Soloviev MM, Canela EI, Mallol J, Chan WY, Lluis C, McIlhinney RA, Franco R. Metabotropic glutamate 1alpha and adenosine A1 receptors assemble into functionally interacting complexes. J Biol Chem. 2001;276:18345–51. doi: 10.1074/jbc.M006960200. [DOI] [PubMed] [Google Scholar]
  • [6].Yoshioka K, Saitoh O, Nakata H. Heteromeric association creates a P2Y-like adenosine receptor. Proc Natl Acad Sci USA. 2001;98:7617–22. doi: 10.1073/pnas.121587098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Ferré S, Karcz-Kubicha M, Hope BT, Popoli P, Burgueno J, Gutierrez MA, Casado V, Fuxe K, Goldberg SR, Lluis C, Franco R, Ciruela F. Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proc Natl Acad Sci USA. 2002;99:11940–5. doi: 10.1073/pnas.172393799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Hillion J, Canals M, Torvinen M, Casado V, Scott R, Terasmaa A, Hansson A, Watson S, Olah ME, Mallol J, Canela EI, Zoli M, Agnati LF, Ibanez CF, Lluis C, Franco R, Ferré S, Fuxe K. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem. 2002;277:18091–7. doi: 10.1074/jbc.M107731200. [DOI] [PubMed] [Google Scholar]
  • [9].Agnati LF, Ferré S, Lluis C, Franco R, Fuxe K. Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons. Pharmacol Rev. 2003;55:509–50. doi: 10.1124/pr.55.3.2. [DOI] [PubMed] [Google Scholar]
  • [10].Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, Neve K, Fuxe K, Agnati LF, Woods AS, Ferré S, Lluis C, Bouvier M, Franco R. Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem. 2003;278:46741–9. doi: 10.1074/jbc.M306451200. [DOI] [PubMed] [Google Scholar]
  • [11].Kamiya T, Saitoh O, Yoshioka K, Nakata H. Oligomerization of adenosine A2A and dopamine D2 receptors in living cells. Biochem Biophys Res Commun. 27(306):544–9. doi: 10.1016/s0006-291x(03)00991-4. [DOI] [PubMed] [Google Scholar]
  • [12].Ciruela F, Casado V, Rodrigues RJ, Lujan R, Burgueno J, Canals M, Borycz J, Rebola N, Goldberg SR, Mallol J, Cortes A, Canela EI, Lopez-Gimenez JF, Milligan G, Lluis C, Cunha RA, Ferré S, Franco R. Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J Neurosci. 2006;26:2080–7. doi: 10.1523/JNEUROSCI.3574-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Carriba P, Ortiz O, Patkar K, Justinova Z, Stroik J, Themann A, Muller C, Woods AS, Hope BT, Ciruela F, Casado V, Canela EI, Lluis C, Goldberg SR, Moratalla R, Franco R, Ferré S. Striatal Adenosine A(2A) and Cannabinoid CB(1) Receptors Form Functional Heteromeric Complexes that Mediate the Motor Effects of Cannabinoids. Neuropsychopharmacology. 2007;32:2249–59. doi: 10.1038/sj.npp.1301375. [DOI] [PubMed] [Google Scholar]
  • [14].Ferré S, Ciruela F, Woods AS, Lluis C, Franco R. Functional relevance of neurotransmitter receptor heteromers in the central nervous system. Trends Neurosci. 2007;30:440–6. doi: 10.1016/j.tins.2007.07.001. [DOI] [PubMed] [Google Scholar]
  • [15].Gerfen CR. Basal Ganglia. In: Paxinos G, editor. The Rat Nervous System. Elsevier Academic Press; Amsterdam: 2004. pp. 445–508. [Google Scholar]
  • [16].Ferré S, Agnati LF, Ciruela F, Lluis C, Woods AS, Fuxe K, Franco R. Neurotransmitter receptor heteromers and their integrative role in ‘local modules’: The striatal spine module. Brain Res Rev. 2007;55:55–67. doi: 10.1016/j.brainresrev.2007.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Ferré S, Borycz J, Goldberg SR, Hope BT, Morales M, Lluis C, Franco R, Ciruela F, Cunha R. Role of adenosine in the control of homosynaptic plasticity in striatal excitatory synapses. J Integr Neurosci. 2005;4:445–64. doi: 10.1142/s0219635205000987. [DOI] [PubMed] [Google Scholar]
  • [18].Newman EA. New roles for astrocytes: Regulation of synaptic transmission. Trends Neurosci. 2003;26:536–42. doi: 10.1016/S0166-2236(03)00237-6. [DOI] [PubMed] [Google Scholar]
  • [19].Hertz L, Zielke R. Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci. 2004;27:735–43. doi: 10.1016/j.tins.2004.10.008. [DOI] [PubMed] [Google Scholar]
  • [20].Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG. Astrocytic purinergic signaling coordinates synaptic networks. Science. 2005;310:113–6. doi: 10.1126/science.1116916. [DOI] [PubMed] [Google Scholar]
  • [21].Schiffmann SN, Jacobs O, Vanderhaeghen JJ. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J Neurochem. 1991;57:1062–1067. doi: 10.1111/j.1471-4159.1991.tb08257.x. [DOI] [PubMed] [Google Scholar]
  • [22].Schiffmann SN, Vanderhaeghen JJ. Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J Neurosci. 1993;13:1080–1087. doi: 10.1523/JNEUROSCI.13-03-01080.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Ferré S, Fredholm BB, Morelli M, Popoli P, Fuxe K. Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci. 1997;20:482–7. doi: 10.1016/s0166-2236(97)01096-5. [DOI] [PubMed] [Google Scholar]
  • [24].Ferré S, Ciruela F, Quiroz C, Lujan R, Popoli P, Cunha RA, Agnati LF, Fuxe K, Woods AS, Lluis C, Franco R. Adenosine receptor heteromers and their integrative role in striatal function. The Scientific WorldJOURNAL. 2007;7:74–85. doi: 10.1100/tsw.2007.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Franco R, Casado V, Cortes A, Ferrada C, Mallol J, Woods A, Lluis C, Canela EI, Ferré S. Basic concepts in G-protein-coupled receptor homo- and heteromerization. The Scientific World JOURNAL. 2007;7:48–57. doi: 10.1100/tsw.2007.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Ciruela F, Burgueno J, Casado V, Canals M, Marcelino D, Goldberg SR, Bader M, Fuxe K, Agnati LF, Lluis C, Franco R, Ferré S, Woods AS. Combining Mass spectrometry and pull-down techniques for the study of receptor heteromerization. Direct epitope-epitope electrostatic interactions between adenosine A2A and dopamine D2 receptors. Anal Chem. 2004;76:5354–63. doi: 10.1021/ac049295f. [DOI] [PubMed] [Google Scholar]
  • [27].Woods AS, Ferré S. The amazing stability of the arginine-phosphate electrostatic interaction. J Proteome Res. 2005;4:1397–402. doi: 10.1021/pr050077s. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Ferré S, von Euler G, Johansson B, Fredholm BB, Fuxe K. Stimulation of high affinity adenosine A-2 receptors decreases the affinity of dopamine D-2 receptors in rat striatal membranes. Proc Natl Acad Sci USA. 1991;88:7238–41. doi: 10.1073/pnas.88.16.7238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Dasgupta S, Ferré S, Kull B, Hendlund P, Finnman U-B, Ahlberg S, Arenas E, Fredholm BB, Fuxe K. Adenosine A2A receptors modulate the binding characteristics of dopamine D2 receptors in stably cotransfected fibroblast cells. Eur J Pharmacol. 1996;316:325–31. doi: 10.1016/s0014-2999(96)00665-6. [DOI] [PubMed] [Google Scholar]
  • [30].Dixon AK, Widdowson L, Richardson PJ. Desensitisation of the adenosine A1 receptor by the A2A receptor in the rat striatum. J Neurochem. 1997;69:315–21. doi: 10.1046/j.1471-4159.1997.69010315.x. [DOI] [PubMed] [Google Scholar]
  • [31].Kull B, Ferré S, Arslan G, Svenningsson P, Fuxe K, Owman C, Fredholm BB. Reciprocal interactions between adenosine A2A and dopamine D2 receptors in CHO cells co-transfected with the two receptors. Biochem Pharmacol. 1999;58:1035–45. doi: 10.1016/s0006-2952(99)00184-7. [DOI] [PubMed] [Google Scholar]
  • [32].Salim H, Ferré S, Dalal A, Peterfreund RA, Fuxe K, Vincent JD, Lledo P-M. Activation of adenosine A1 and A2A receptors modulates dopamine D2 receptor-induced responses in stably cotransfected human neuroblastoma cells. J Neurochem. 2000;74:432–9. doi: 10.1046/j.1471-4159.2000.0740432.x. [DOI] [PubMed] [Google Scholar]
  • [33].Díaz-Cabiale Z, Hurd Y, Guidolin D, Finnman U-B, Zoli M, Vanderhaeghen J-J, Fuxe K, Ferré S. Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum. NeuroReport. 2001;12:1831–4. doi: 10.1097/00001756-200107030-00014. [DOI] [PubMed] [Google Scholar]
  • [34].Kudlacek O, Just H, Korkhov VM, Vartian N, Klinger M, Pankevych H, Yang Q, Nanoff C, Freissmuth M, Boehm S. The human D2 dopamine receptor synergizes with the A2A adenosine receptor to stimulate adenylyl cyclase in PC12 cells. Neuropsychopharmacology. 2003;28:1317–27. doi: 10.1038/sj.npp.1300181. [DOI] [PubMed] [Google Scholar]
  • [35].Ferré S, O’Connor WT, Fuxe K, Ungerstedt U. The striopallidal neuron: a main locus for adenosine-dopamine interactions in the brain. J Neurosci. 1993;13:5402–6. doi: 10.1523/JNEUROSCI.13-12-05402.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Ferré S, O’Connor WT, Snaprud P, Ungerstedt U, Fuxe K. Antagonistic interaction between adenosine A2a and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia. Neuroscience. 1994;63:765–73. doi: 10.1016/0306-4522(94)90521-5. [DOI] [PubMed] [Google Scholar]
  • [37].Surmeier DJ, Ding J, Day M, Wang Z, Shen W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 2007;30:228–35. doi: 10.1016/j.tins.2007.03.008. [DOI] [PubMed] [Google Scholar]
  • [38].Ferré S, Herrera-Marschitz M, Grabowska-Andén M, Ungerstedt U, Casas M, Andén N-E. Postsynaptic dopamine/adenosine interaction: I. Adenosine analogues inhibit a D2-mediated behaviour in short-term reserpinized mice. Eur J Pharmacol. 1991;192:30–5. doi: 10.1016/0014-2999(91)90064-w. [DOI] [PubMed] [Google Scholar]
  • [39].Ferré S, Herrera-Marschitz M, Grabowska-Andén M, Ungerstedt U, Casas M, Andén N-E. Postsynaptic dopamine/adenosine interaction: II. Postsynaptic dopamine agonism and adenosine antagonism of methylxanthines in short-term reserpinized mice. Eur J Pharmacol. 1991;192:36–42. doi: 10.1016/0014-2999(91)90065-x. [DOI] [PubMed] [Google Scholar]
  • [40].Rimondini R, Ferré S, Giménez-Llort L, Ögren SO, Fuxe K. Differential effects of selective adenosine A1 and A2A receptor agonists on dopamine receptor agonist-induced behavioural responses in rats. Eur J Pharmacol. 1998;347:153–8. doi: 10.1016/s0014-2999(98)00107-1. [DOI] [PubMed] [Google Scholar]
  • [41].Stromberg I, Popoli P, Müller CE, Ferré S, Fuxe K. Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatum. Eur J Neurosci. 2000;12:4033–7. doi: 10.1046/j.1460-9568.2000.00288.x. [DOI] [PubMed] [Google Scholar]
  • [42].Ferré S, Popoli P, Gimenez-Llort L, Rimondini R, Müller CE, Stromberg I, Ogren SO, Fuxe K. Adenosine/dopamine interaction: implications for the treatment of Parkinson’s disease. Parkinsonism Relat Disord. 2001;7:235–41. doi: 10.1016/s1353-8020(00)00063-8. [DOI] [PubMed] [Google Scholar]
  • [43].Ferré S, Fuxe K, von Euler G, Johansson B, Fredholm BB. Adenosine-dopamine interactions in the brain. Neuroscience. 1992;51:501–12. doi: 10.1016/0306-4522(92)90291-9. [DOI] [PubMed] [Google Scholar]
  • [44].Muller CE, Ferré S. Blocking striatal adenosine A2A receptors: A new strategy for basal ganglia disorders. Recent Pat CNS Drug Disc. 2007;2:1–21. doi: 10.2174/157488907779561772. [DOI] [PubMed] [Google Scholar]
  • [45].Svenningsson P, Lindskog M, Ledent C, Parmentier M, Greengard P, Fredholm BB, Fisone G. Regulation of the phosphorylation of the dopamine- and cAMP- regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors. Proc Natl Acad Sci USA. 2000;97:1856–60. doi: 10.1073/pnas.97.4.1856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Hakansson K, Galdi S, Hendrick J, Snyder G, Greengard P, Fisone G. Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors. J Neurochem. 2006;96:482–8. doi: 10.1111/j.1471-4159.2005.03558.x. [DOI] [PubMed] [Google Scholar]
  • [47].Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O’Dowd BF, George SR. D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA. 2007;104:654–9. doi: 10.1073/pnas.0604049104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Banères JL, Parello J. Structure-based analysis of GPCR function: evidence for a novel pentameric assembly between the dimeric leukotriene B4 receptor BLT1 and the G-protein. J Mol Biol. 2003;329:815–829. doi: 10.1016/s0022-2836(03)00439-x. [DOI] [PubMed] [Google Scholar]
  • [49].Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A. Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J Biol Chem. 2003;278:21655–21662. doi: 10.1074/jbc.M302536200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Herrick-Davis K, Grinde E, Harrigan TJ, Mazurkiewicz JE. Inhibition of serotonin 5-hydroxytryptamine2c receptor function through heterodimerization: receptor dimers bind two molecules of ligand and one G-protein. J Biol Chem. 2005;280:40144–40151. doi: 10.1074/jbc.M507396200. [DOI] [PubMed] [Google Scholar]
  • [51].Franco R, Casado V, Mallol J, Ferrada C, Ferré S, Fuxe K, Cortés A, Ciruela F, Lluis C, Canela EI. The "two-state dimer receptor model". A general model for receptor dimers. Mol Pharmacol. 2006;69:1905–1912. doi: 10.1124/mol.105.020685. [DOI] [PubMed] [Google Scholar]
  • [52].Casado V, Cortes A, Ciruela F, Mallol J, Ferré S, Lluis C, Canela EI, Franco R. Old and new ways to calculate the affinity of agonists and antagonists interacting with G-protein-coupled monomeric and dimeric receptors: The receptor-dimer cooperativity index. Pharmacol Ther. 2007;116:343–354. doi: 10.1016/j.pharmthera.2007.05.010. [DOI] [PubMed] [Google Scholar]
  • [53].Wess J. Molecular basis of receptor/G-protein-coupling selectivity. Pharmacol Ther. 1998;80:231–264. doi: 10.1016/s0163-7258(98)00030-8. [DOI] [PubMed] [Google Scholar]
  • [54].Voss T, Wallner E, Czernilofsky AP, Freissmuth M. Amphipathic alpha-helical structure does not predict the ability of receptor-derived synthetic peptides to interact with guanine nucleotide-binding regulatory proteins. J Biol Chem. 1993;268:4637–4642. [PubMed] [Google Scholar]
  • [55].Bofill-Cardona E, Kudlacek O, Yang Q, Ahorn H, Freissmuth M, Nanoff C. Binding of calmodulin to the D2-dopamine receptor reduces receptor signaling by arresting the G protein activation switch. J Biol Chem. 2000;275:32672–32680. doi: 10.1074/jbc.M002780200. [DOI] [PubMed] [Google Scholar]
  • [56].Liu Y, Buck DC, Macey TA, Lan H, Neve KA. Evidence that calmodulin binding to the dopamine D2 receptor enhances receptor signaling. J Recept Signal Transduct Res. 2007;27:47–65. doi: 10.1080/10799890601094152. [DOI] [PubMed] [Google Scholar]
  • [57].Nishi A, Liu F, Matsuyama S, Hamada M, Higashi H, Nairn AC, Greengard P. Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling. Proc Natl Acad Sci USA. 2003;100:1322–7. doi: 10.1073/pnas.0237126100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Popoli P, Pezzola A, Torvinen M, Reggio R, Pintor A, Scarchili L, Fuxe K, Ferré S. The selective mGlu5 receptor agonist CHPG inhibits quinpirole-induced turning in 6-hydroxydopamine-lesioned rats and modulates the binding characteristics of dopamine D2 receptors in the rat striatum: Interactions with adenosine A2A receptors. Neuropsychopharmacology. 2001;25:505–13. doi: 10.1016/S0893-133X(01)00256-1. [DOI] [PubMed] [Google Scholar]
  • [59].Kachroo A, Orlando LR, Grandy DK, Chen JF, Young AB, Schwarzschild MA. Interactions between metabotropic glutamate 5 and adenosine A2A receptors in normal and parkinsonian mice. J Neurosci. 2005;25:10414–19. doi: 10.1523/JNEUROSCI.3660-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [60].Díaz-Cabiale Z, Vivó M, Del Arco A, O’Connor WT, Harte MK, Müller CE, Martínez E, Popoli P, Fuxe K, Ferré S. Metabotropic glutamate mGlu5 receptor-mediated modulation of the ventral striopallidal GABA pathway. Interactions with adenosine A2A and dopamine D2 receptors. Neurosci Lett. 2002;324:154–8. doi: 10.1016/s0304-3940(02)00179-9. [DOI] [PubMed] [Google Scholar]
  • [61].Lee KW, Hong JH, Choi IY, Che Y, Lee JK, Yang SD, Song CW, Kang HS, Lee JH, Noh JS, Shin HS, Han PL. Impaired D2 dopamine receptor function in mice lacking type 5 adenylyl cyclase. J Neurosci. 2002;22:7931–40. doi: 10.1523/JNEUROSCI.22-18-07931.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [62].Yao L, Arolfo MP, Dohrman DP, Jiang Z, Fan P, Fuchs S, Janak PH, Gordon AS, Diamond I. Betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. Cell. 2002;109:733–43. doi: 10.1016/s0092-8674(02)00763-8. [DOI] [PubMed] [Google Scholar]
  • [63].Ferré S, Diamond I, Goldberg SR, Yao L, Hourani SMO, Huang ZL, Urade Y, Kitchen I. Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry. Implications for drug addiction, sleep and pain. Prog Neurobiol. 2007;83:332–47. doi: 10.1016/j.pneurobio.2007.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [64].Blumer JB, Cismowski MJ, Sato M, Lanier SM. AGS proteins: receptor- independent activators of G-protein signaling. Trends Pharmacol Sci. 2005;26:470–6. doi: 10.1016/j.tips.2005.07.003. [DOI] [PubMed] [Google Scholar]
  • [65].Chern Y. Regulation of adenylyl cyclase in the central nervous system. Cell Signal. 2000;12:195–204. doi: 10.1016/s0898-6568(99)00084-4. [DOI] [PubMed] [Google Scholar]
  • [66].Bowers MS, McFarland K, Lake RW, Peterson YK, Lapish CC, Gregory ML, Lanier SM, Kalivas PW. Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking. Neuron. 2004;42:269–81. doi: 10.1016/s0896-6273(04)00159-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].Yao L, McFarland K, Fan P, Jiang Z, Inoue Y, Diamond I. Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior. Proc Natl Acad Sci USA. 2005;102:8746–51. doi: 10.1073/pnas.0503419102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [68].Mayfield RD, Suzuki F, Zahniser NR. Adenosine A2a receptor modulation of electrically evoked endogenous GABA release from slices of rat globus pallidus. J Neurochem. 1993;60:2334–7. doi: 10.1111/j.1471-4159.1993.tb03526.x. [DOI] [PubMed] [Google Scholar]
  • [69].Ochi M, Koga K, Kurokawa M, Kase H, Nakamura J, Kuwana Y. Systemic administration of adenosine A(2A) receptor antagonist reverses increased GABA release in the globus pallidus of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study. Neuroscience. 2000;100:53–62. doi: 10.1016/s0306-4522(00)00250-5. [DOI] [PubMed] [Google Scholar]
  • [70].Shindou T, Nonaka H, Richardson PJ, Mori A, Kase H, Ichimura M. Presynaptic adenosine A(2A) receptors enhance GABAergic synaptic transmission via a cyclic AMP dependent mechanism in the rat globus pallidus. Br. J. Pharmacol. 2002;136:296–302. doi: 10.1038/sj.bjp.0704702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [71].Leenders AG, Sheng ZH. Modulation of neurotransmitter release by the second messenger-activated protein kinases: implications for presynaptic plasticity. Pharmacol Ther. 2005;105:69–84. doi: 10.1016/j.pharmthera.2004.10.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [72].Gubitz AK, Widdowson L, Kurokawa M, Kirkpatrick KA, Richardson PJ. Dual signalling by the adenosine A2a receptor involves activation of both N- and P- type calcium channels by different G proteins and protein kinases in the same striatal nerve terminals. J Neurochem. 1996;67:374–81. doi: 10.1046/j.1471-4159.1996.67010374.x. [DOI] [PubMed] [Google Scholar]
  • [73].Okada M, Nutt DJ, Murakami T, Zhu G, Kamata A, Kawata Y, Kaneko S. Adenosine receptor subtypes modulate two major functional pathways for hippocampal serotonin release. J Neurosci. 2001;21:628–40. doi: 10.1523/JNEUROSCI.21-02-00628.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [74].Simola N, Fenu S, Baraldi PG, Tabrizi MA, Morelli M. Involvement of globus pallidus in the antiparkinsonian effects of adenosine A(2A) receptor antagonists. Exp Neurol. 2006;202:255–7. doi: 10.1016/j.expneurol.2006.05.015. [DOI] [PubMed] [Google Scholar]
  • [75].Tanganelli S, Sandager Nielsen K, Ferraro L, Antonelli T, Kehr J, Franco R, Ferré S, Agnati LF, Fuxe K, Scheel-Krüger J. Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson’s disease. Parkinsonism Relat Disord. 2004;10:273–80. doi: 10.1016/j.parkreldis.2004.02.015. [DOI] [PubMed] [Google Scholar]
  • [76].Rodrigues RJ, Alfaro TM, Rebola N, Oliveira CR, Cunha RA. Co-localization and functional interaction between adenosine A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum. J Neurochem. 2005;92:433–41. doi: 10.1111/j.1471-4159.2004.02887.x. [DOI] [PubMed] [Google Scholar]
  • [77].Tozzi A, Tscherter A, Belcastro V, Tantucci M, Costa C, Picconi B, Centonze D, Calabresi P, Borsini F. Interaction of A2A adenosine and D2 dopamine receptors modulates corticostriatal glutamatergic transmission. Neuropharmacology. 2007;53:783–9. doi: 10.1016/j.neuropharm.2007.08.006. [DOI] [PubMed] [Google Scholar]

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