Interactions between Metabotropic Glutamate 5 and Adenosine A<sub>2A</sub>Receptors in Normal and Parkinsonian Mice

Kachroo, Anil; Orlando, Lianna; Grandy, David K.; Chen, Jiang‐Fan; Young, Anne B.; Schwarzschild, Michael A.

doi:10.1523/jneurosci.3660-05.2005

Cited by 136 publications

(107 citation statements)

References 36 publications

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“…Immunostaining for TH was performed as described previously (43). Five weeks after 6-OHDA lesioning mice were killed by rapid cervical dislocation.…”

Section: Methodsmentioning

confidence: 99%

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Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Chen

Burdett

Desjardins

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

112

121

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Urate is the end product of purine metabolism in humans, owing to the evolutionary disruption of the gene encoding urate oxidase (UOx). Elevated urate can cause gout and urolithiasis and is associated with cardiovascular and other diseases. However, urate also possesses antioxidant and neuroprotective properties. Recent convergence of epidemiological and clinical data has identified urate as a predictor of both reduced risk and favorable progression of Parkinson's disease (PD). In rodents, functional UOx catalyzes urate oxidation to allantoin. We found that UOx KO mice with a constitutive mutation of the gene have increased concentrations of brain urate. By contrast, UOx transgenic (Tg) mice overexpressing the enzyme have reduced brain urate concentrations. Effects of the complementary UOx manipulations were assessed in a mouse intrastriatal 6-hydroxydopamine (6-OHDA) model of hemiparkinsonism. UOx KO mice exhibit attenuated toxic effects of 6-OHDA on nigral dopaminergic cell counts, striatal dopamine content, and rotational behavior. Conversely, Tg overexpression of UOx exacerbates these morphological, neurochemical, and functional lesions of the dopaminergic nigrostriatal pathway. Together our data support a neuroprotective role of endogenous urate in dopaminergic neurons and strengthen the rationale for developing urate-elevating strategies as potential disease-modifying therapy for PD.U rate, the anionic component of uric acid, predominates at physiological pH. As an apparent consequence of mutations in the urate oxidase (UOx) gene during primate evolution, urate constitutes the enzymatic end product of purine metabolism in humans (1). There remains controversy over how the loss of UOx activity and the resultant high urate concentrations in hominoids may have been beneficial and whether it still is. On one hand, urate is considered a pathogenic factor in gout, urolithiasis, and nephropathy, and hyperuricemia is associated with other medical conditions, such as hypertension, cardiovascular disease, and metabolic syndrome (2). On the other hand, the loss of UOx activity through multiple independent mutations in hominoids presumably conferred evolutionary advantages. Urate possesses potent antioxidant properties. High urate levels may have provided an antioxidant defense against aging and cancer, thereby contributing to a prolonged hominoid life span (3). In addition, increased urate may mediate blood pressure homeostasis in low-salt environments. Furthermore, higher urate has been suggested to enhance human intelligence or motivational behaviors or promote neuronal integrity and function (4).Recently a series of population and clinical epidemiology studies have lent support to a potential neuroprotective effect of urate (5,6). These studies demonstrated a robust inverse link between urate levels and both the risk and clinical progression of Parkinson's disease (PD), one of the most common neurodegenerative diseases. Given the putative role of oxidative stress in the pathogenesis of PD (7), these studies have i...

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“…Immunostaining for TH was performed as described previously (43). Five weeks after 6-OHDA lesioning mice were killed by rapid cervical dislocation.…”

Section: Methodsmentioning

confidence: 99%

“…T1299) at 1:800. Stereologic analysis was performed with the investigator blinded to genotypes using the Bioquant Image Analysis System (R&M Biometrics) (43). For each animal, the SN on both sides of the brain was analyzed.…”

Section: Methodsmentioning

confidence: 99%

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Chen

Burdett

Desjardins

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

112

121

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“…A 1 and A 2A receptors are expressed in the brain, with A 2A being primarily localized to the dorsal striatum, nucleus accumbens, olfactory tubercle, and external globus pallidus (GPe) (Schwarzschild et al, 2006). In the striatum, A 2A receptors are co-localized with dopamine D 2 receptors, the peptide enkephalin, and the metabotropic glutamate receptor 5 (mGluR5), with which they functionally interact in dendrites and spines of medium spiny striatopallidal neurons within the indirect pathway of the basal ganglia (Fuxe et al, 2003(Fuxe et al, , 2007a(Fuxe et al, , b, 2010aTanganelli et al, 2004;Kachroo et al, 2005;Simola et al, 2008;Agnati et al, 2010;Tozzi et al, 2011) (Figure 1). D 2 and A 2A receptors have opposite effects on the activity of striatal neurons (Ferré et al, 1997).…”

Section: Non-dopaminergic Therapiesmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…In vivo experiments demonstrated that costimulation of A 2A and mGlu 5 receptors, with the central administration of selective agonists, allows A 2A receptor to get rid of the tonic inhibitory effect of D 2 receptor and signal through cAMP-PKA pathway [7]. Since these A 2A -mGlu 5 -D 2 receptor interactions can be demonstrated in animal models of Parkinson's disease [58,59], we postulated that co-administration of A 2A and mGlu 5 receptor antagonists could be used as a therapeutic strategy in this disease [58]. Similarly, in vivo microdialysis experiments have shown that A 2A -mGlu 5 -D 2 receptor interactions modulate the function of the GABAergic enkephalinergic neurons of the nucleus accumbens [60], which can have implications for schizophrenia and drug addiction.…”

Section: Coexistence Of the Reciprocal Antagonistic A 2a -D 2 Receptomentioning

confidence: 99%

An Update on Adenosine A2A-Dopamine D2 Receptor Interactions: Implications for the Function of G Protein-Coupled Receptors

Ferré¹,

Quiroz²,

Woods³

et al. 2008

CPD

227

185

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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 neurons. 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.Key Words: Adenosine A 2A Receptor, Dopamine D 2 Receptor, G Protein-Coupled Receptors, Receptor Heteromers, Striatum, Basal Ganglia Disorders, Drug Addiction. LOCALIZATION OF THE A 2A -D 2 RECEPTOR HETERO-MERApplying 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 A 1 , A 2A , A 2B and A 3 receptors ) , A 1 and A 2A receptors are the main targets for the physiological effects of adenosine in the brain [2]. A 1 receptor is widely distributed in the brain, including the striatum, while A 2A 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 A 1 and A 2A receptors to heteromerize with themselves and with other GPCRs, such as dopamine, glutamate, cannabinoid and ATP receptors [4][5][6][7][8][9][10][11][12][13][14]. The present review focuses on the role of one particular adenosine receptor heteromer, the one constituted by the A 2A and the dopamine D 2 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 compac...

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Interactions between Metabotropic Glutamate 5 and Adenosine A_2AReceptors in Normal and Parkinsonian Mice

Cited by 136 publications

References 36 publications

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

An Update on Adenosine A2A-Dopamine D2 Receptor Interactions: Implications for the Function of G Protein-Coupled Receptors

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Interactions between Metabotropic Glutamate 5 and Adenosine A2AReceptors in Normal and Parkinsonian Mice

Cited by 136 publications

References 36 publications

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

An Update on Adenosine A2A-Dopamine D2 Receptor Interactions: Implications for the Function of G Protein-Coupled Receptors

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Product

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Interactions between Metabotropic Glutamate 5 and Adenosine A_2AReceptors in Normal and Parkinsonian Mice