Pharmacological characterization of metabotropic glutamate receptors linked to the inhibition of adenylate cyclase activity in rat striatal slices

Schaffhauser, Hervé; Cartmell, Jayne; Jakob-Røtne, Roland; Mutel, Vincent

doi:10.1016/s0028-3908(97)00079-8

Cited by 27 publications

(18 citation statements)

References 38 publications

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“…1C), consistent with the potency of this compound at group II mGluRs. The steep slope of the concentration-response curve for LY354740 is consistent with the dose-response relationship reported for a number other effects of this drug in both recom-binant and native systems Schaffhauser et al, 1997;Schoepp et al, 1997). The reduction of EPSC amplitude was mimicked by two other highly selective agonists of group II mGluRs, 2 R,4 R-APDC (Schoepp et al, 1995) and DCG-IV (Hayashi et al, 1993;Gereau and Conn, 1995a) (Fig.…”

Section: Activation Of Group II Mglurs Inhibits Transmission At the Ssupporting

confidence: 86%

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Bradley¹,

Marino²,

Wittmann

et al. 2000

J. Neurosci.

130

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Loss of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) leads to increased activity of glutamatergic neurons in the subthalamic nucleus (STN). Recent studies reveal that the resultant increase in STN-induced excitation of basal ganglia output nuclei is responsible for the disabling motor impairment characteristic of PD. On the basis of this, it is possible that any manipulation that reduces activity at excitatory STN synapses onto basal ganglia output nuclei could be useful in the treatment of PD. We now report that group II metabotropic glutamate receptors (mGluRs) are presynaptically localized on STN terminals and that activation of these receptors inhibits excitatory transmission at STN synapses. In agreement with the hypothesis that this could provide a therapeutic benefit in PD, a selective agonist of group II mGluRs induces a dramatic reversal of catalepsy in a rat model of PD. These results raise the exciting possibility that selective agonists of group II mGluRs could provide an entirely new approach to the treatment of PD. These novel therapeutic agents would provide a noninvasive pharmacological treatment that does not involve the manipulation of dopaminergic systems, thus avoiding the problems associated with current therapies. Key words: substantia nigra pars reticulata; subthalamic nucleus; group II metabotropic glutamate receptors; Parkinson's disease; catalepsy; presynaptic inhibitionParkinson's disease (PD) is a common neurodegenerative disorder characterized by disabling motor impairments including tremor, rigidity, and bradykinesia. The primary pathological change giving rise to the symptoms of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta that modulate the function of neurons in the striatum and other nuclei in the basal ganglia (BG) motor circuit. Currently, the most effective pharmacological agents for the treatment of PD include levodopa (L-DOPA), the immediate precursor of dopamine, and other drugs that replace the lost dopaminergic modulation of BG function (Poewe and Granata, 1997). Unfortunately, dopamine replacement therapy ultimately fails in most patients because of loss of efficacy with progression of the disease and severe motor and psychiatric side effects (Poewe et al., 1986). Because of this, a great deal of effort has been focused on developing new approaches for the treatment of PD.Recent studies reveal that loss of nigrostriatal dopamine neurons results in a series of neurophysiological changes that lead to overactivity of a critical nucleus in the BG motor circuit termed the subthalamic nucleus (STN). The STN contains glutamatergic projection neurons that provide the major excitatory input to the globus pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr), the major output nuclei of the basal ganglia. Increased activity of STN neurons leads to an increase in glutamate release at STN synapses onto GABAergic projection neurons in the output nuclei. This glutamate-mediated overexcitation of BG output ultima...

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Section: Activation Of Group II Mglurs Inhibits Transmission At the Ssupporting

confidence: 86%

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Bradley¹,

Marino²,

Wittmann

et al. 2000

J. Neurosci.

130

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“…Activation of group I mGluRs results in the stimulation of phosphoinositide hydrolysis, whereas activation of group II and group III mGluRs results in inhibition of cAMP formation (31,32). Like other groups of mGluRs, group I mGluRs exhibit a heterogeneous distribution in the central nervous system (33,34). In the striatum, an area richly innervated with glutamatergic afferents from widespread regions of the forebrain, morphological studies show a dense distribution of group I mGluRs (35).…”

Section: Discussionmentioning

confidence: 99%

Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors

Liu

Hong

Ule

et al. 2001

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

119

129

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Cyclin-dependent kinase 5 (Cdk5) is a multifunctional neuronal protein kinase that is required for neurite outgrowth and cortical lamination and that plays an important role in dopaminergic signaling in the neostriatum through phosphorylation of Thr-75 of DARPP-32 (dopamine and cAMP-regulated phosphoprotein, molecular mass 32 kDa). Casein kinase 1 (CK1) has been implicated in a variety of cellular functions such as DNA repair, circadian rhythm, and intracellular trafficking. In the neostriatum, CK1 has been found to phosphorylate Ser-137 of DARPP-32. However, first messengers for the regulation of Cdk5 or CK1 have remained unknown. Here we report that both Cdk5 and CK1 are regulated by metabotropic glutamate receptors (mGluRs) in neostriatal neurons. (S)-3,5-dihydroxyphenylglycine (DHPG), an agonist for group I mGluRs, increased Cdk5 and CK1 activities in neostriatal slices, leading to the enhanced phosphorylation of Thr-75 and Ser-137 of DARPP-32, respectively. The effect of DHPG on Thr-75, but not on Ser-137, was blocked by a Cdk5-specific inhibitor, butyrolactone. In contrast, the effects of DHPG on both Thr-75 and Ser-137 were blocked by CK1-7 and IC261, specific inhibitors of CK1, suggesting that activation of Cdk5 by mGluRs requires CK1 activity. In support of this possibility, the DHPG-induced increase in Cdk5 activity, measured in extracts of neostriatal slices, was abolished by CK1-7 and IC261. Treatment of acutely dissociated neurons with DHPG enhanced voltage-dependent Ca 2؉ currents. This enhancement was eliminated by either butyrolactone or CK1-7 and was absent in DARPP-32 knockout mice. Together these results indicate that a CK1-Cdk5-DARPP-32 cascade may be involved in the regulation by mGluR agonists of Ca 2؉ channels. C yclin-dependent kinase 5 (Cdk5)͞p35 plays a variety of roles in the developing and adult nervous system (1-3). Studies of mice in which the gene encoding either Cdk5 or p35 has been disrupted have indicated that both mutants exhibit abnormalities in the laminar structure of the cerebral cortex (4, 5). Conversion of p35 to p25 by the action of calpain causes altered localization and prolonged activation of Cdk5 (6-9). Cdk5 phosphorylates DARPP-32 (dopamine-and cAMP-regulated-phosphoprotein, molecular mass 32 kDa) on Thr-75 (10, 11). Phosphorylation at Thr-34 by cAMP-dependent protein kinase (PKA) converts DARPP-32 into an inhibitor of protein phosphatase-1 (PP-1), a process that is critical for the actions of dopamine in the neostriatum (12). Phosphorylation of Thr-75 by Cdk5 converts DARPP-32 into an inhibitor of PKA, reducing phosphorylation of DARPP-32 at Thr-34, and modulating the DARPP-32͞PP-1 cascade (10).Casein kinase 1 (CK1) was one of the first serine͞threonine protein kinases to be isolated and characterized (13). It is a ubiquitous enzyme that can be found in the nucleus and the cytosol and bound to the cytoskeleton and membranes. The CK1 family consists of multiple isoforms encoded by seven distinct genes (CK1␣, ␤, ␥1, ␥2, ␥3, ␦, and ). These isoforms exhibit more than ...

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“…At Axon terminal. Scale bars: 500 nm modulate neuronal excitability and plasticity via intracellular mechanisms such as modulation of ion channels (e.g., potassium) and adenylyl cyclase (Anwyl 1999;Schaffhauser et al 1997;Schoepp et al 1998). Thus, blockade of group II mGlu receptors by LY341495 may increase neuronal activation via multiple mechanisms involving pre-and/or postsynaptic sites either in neurons or in glial cells.…”

Section: Ly341495-induced C-fos Expression In Wt Micementioning

confidence: 99%

Individual contribution of metabotropic glutamate receptor (mGlu) 2 and 3 to c-Fos expression pattern evoked by mGlu2/3 antagonism

et al. 2008

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Objectives and materials and methods The aims of the present study were (1) to determine the neuronal activation pattern elicited by the group II mGlu antagonist LY341495 and (2) to evaluate the contribution of each group II mGlu subtype by using wild-type (WT) and knockout (KO) mice lacking either mGlu2 or mGlu3. c-Fos expression was used as a marker of neuronal activation. Results and discussion In WT mice, LY341495 induced widespread c-Fos expression in 68 out of 92 brain areas, including limbic areas such as the amygdala, septum, prefrontal cortex, and hippocampus. LY341495-induced cFos response was markedly decreased in the medial part of the central amygdala (CeM) and lateral septum (LS) in mGlu3-KO mice, as well as in the lateral parabrachial nucleus (LPB) in both KO strains. In the majority of investigated areas, LY341495-induced c-Fos expression was similar in KO and WT mice. Analysis of the cellular and subcellular distribution of mGlu2 and mGlu3 revealed a prevailing presence of mGlu3-immunoreactivity in the CeM in glial processes and in postsynapstic neuronal elements, whereas only rare presynaptic axon terminals were found immunoreactive for mGlu2. Conclusion In conclusion, our data indicate that group II mGlu blockade increases neuronal activation in a variety of brain areas, including many stress-and anxiety-related areas. The activation of two key brain areas, the CeM and LS, is mediated via mGlu3, while activation in the LPB involves both subtypes. Moreover, in the majority of investigated areas, LY341495-mediated neuronal activation appears to require a complex cross talk between group II mGlu subtypes or the action of LY341495 on additional receptors.

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Pharmacological characterization of metabotropic glutamate receptors linked to the inhibition of adenylate cyclase activity in rat striatal slices

Cited by 27 publications

References 38 publications

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors

Individual contribution of metabotropic glutamate receptor (mGlu) 2 and 3 to c-Fos expression pattern evoked by mGlu2/3 antagonism

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