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

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253

226

Neurodegeneration, a result of multiple dysregulatory events, is a lengthy multistep process manifested by accrual of mutant variants and abnormal expression, posttranslational modification, and processing of certain proteins. Accumulation of these dysregulated processes requires a mechanism that maintains their functional stability and allows the evolution of the neurodegenerative phenotype. In malignant cells, the capacity to buffer transformation has been attributed to heat-shock protein 90 (Hsp90). Although normal proteins seem to require limited assistance from the chaperone, their aberrant counterparts seem to be highly dependent on Hsp90. Whereas enhanced Hsp90 affinity for mutated or functionally deregulated client proteins has been observed for several oncoproteins, it is unknown whether Hsp90 plays a similar role for neuronal proteins and thus maintains and facilitates the transformed phenotype in neurodegenerative diseases. Tauopathies are neurodegenerative diseases characterized by aberrant phosphorylation and/or expression of Tau protein, leading to a timedependent accumulation of Tau aggregates and subsequent neuronal death. Here, we show that the stability of p35, a neuronal protein that activates cyclin-dependent protein kinase 5 through complex formation leading to aberrant Tau phosphorylation, and that of mutant but not WT Tau protein is maintained in tauopathies by Hsp90. Inhibition of Hsp90 in cellular and mouse models of tauopathies leads to a reduction of the pathogenic activity of these proteins and results in elimination of aggregated Tau. The results identify important roles played by Hsp90 in maintaining and facilitating the degenerative phenotype in these diseases and provide a common principle governing cancer and neurodegenerative diseases.cyclin-dependent protein kinase 5 ͉ neurodegeneration ͉ Tau

Section: Primary Neuronal and Cos-7 Cell Cultures And Incubation Withmentioning

confidence: 99%

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

Luo

Dou

Rodina

et al. 2007

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253

226

“…We have recently reported that, by activating casein kinase 1 (CK1) in a PLC-dependent manner, group I mGlu receptors cause an increase in the phosphorylation of DARPP-32 at Ser-137 (17,18). Moreover, by activating cyclin-dependent kinase 5 (Cdk5), this activation of CK1 causes an increase in the phosphorylation of DARPP-32 at Thr-75 (17).…”

Section: Activation Of Intracellular Signaling By Mglu5 Receptors Invmentioning

confidence: 99%

Metabotropic mGlu5 receptors regulate adenosine A _2A receptor signaling

Nishi

Liu

Matsuyama

et al. 2003

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132

D opamine-and cAMP-regulated phosphoprotein of M r 32,000 (DARPP-32) is a signal transduction molecule that is selectively enriched in medium-sized spiny neurons in neostriatum, and plays an obligatory role in dopaminergic signaling. Mice lacking DARPP-32 exhibit profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse and antipsychotic medication, demonstrating the importance of DARPP-32 in most of the actions of dopamine (1).When DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) on Thr-34, it is converted into a potent inhibitor of protein phosphatase-1, and thereby controls the phosphorylation state and activity of many downstream physiological effectors, including various neurotransmitter receptors and voltage-gated ion channels (for review, see ref.2). Phosphorylation and dephosphorylation of DARPP-32 at Thr-34 are regulated by dopamine, adenosine, glutamate, serotonin, and other neurotransmitters. For example, dopamine, by activating dopamine D1-type receptors (3), and adenosine, by activating adenosine A 2A receptors (4), stimulate the phosphorylation of DARPP-32 at Thr-34.Metabotropic glutamate (mGlu) receptors are subdivided into three groups on the basis of agonist pharmacology, sequence homology, and G-protein effector coupling: group I (mGlu1 and mGlu5 receptors), group II (mGlu2 and mGlu3 receptors), and group III (mGlu4, mGlu6, mGlu7, and mGlu8 receptors; ref. 5). Group I mGlu receptors are coupled to the phospholipase C (PLC) pathway (6), the extracellular signal-regulated kinase (ERK) pathway (7), and the p38 pathway (8); group II and III mGlu receptors are negatively coupled to adenylyl cyclase (9). Individual subtypes of mGlu receptors are assumed to mediate distinct facilitatory (group I) or inhibitory (group II and III) actions on neuronal transmission (10). Recently, mGlu receptors were shown to be involved in cocaine self-administration (11) and methamphetamine-induced neurotoxicity (12). However, the molecular mechanisms underlying the actions of mGlu receptors are not clearly understood. In this study, we investigated the regulation of DARPP-32 phosphorylation at Thr-34 by mGlu receptors by using neostriatal slices. The results obtained indicate that the actions of mGlu5 receptors are linked to A 2A adenosine receptors by means of a mechanism involving the ERK cascade.

“…Equal amounts of protein were processed by using 10% acrylamide gels as described (17). Immunoblotting was carried out with phosphorylation-state-specific antibodies against phospho-Thr-34-DARPP-32 (18), phospho-Thr-75-DARPP-32 (9), phospho-Ser-137-DARPP-32 (19), phospho-Ser-831-GluR1 (Upstate Biotechnology, Lake Placid, NY), phospho-Ser-845-GluR1 (Upstate Biotechnology), or antibodies that are not phosphorylation-state-specific against total DARPP-32 (20) and total GluR1 (Upstate Biotechnology). Antibody binding was detected by enhanced chemiluminescence (ECL; Amersham Pharmacia) and quantified by densitometry, using National Institutes of Health IMAGE 1.61 software.…”

Section: Preparation and Treatment Of Slices From Hippocampus Prefromentioning

confidence: 99%

Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac)

Svenningsson

Tzavara

Witkin

et al. 2002

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217

126

Fluoxetine (Prozac) is the most widely prescribed medication for the treatment of depression. Nevertheless, little is known about the molecular basis of its clinical efficacy, apart from the fact that fluoxetine increases the synaptic availability of serotonin. Here we show that, in vivo, fluoxetine, given either acutely or chronically, regulates the phosphorylation state of dopamine-and cAMPregulated phosphoprotein of M r 32,000 (DARPP-32) at multiple sites in prefrontal cortex, hippocampus, and striatum. Acute administration of fluoxetine increases phosphorylation of DARPP-32 at the protein kinase A site, Thr-34, and at the casein kinase-1 site, Ser-137, and decreases phosphorylation at the cyclin-dependent kinase 5 site, Thr-75. Each of these changes contributes, through distinct signaling pathways, to increased inhibition of protein phosphatase-1, a major serine͞threonine protein phosphatase in the brain. Fluoxetine also increases phosphorylation of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 at Ser-831 and Ser-845. Both the fluoxetinemediated increase in AMPA receptor phosphorylation at Ser-845-GluR1 and the beneficial responsiveness to fluoxetine in an animal test of antidepressant efficacy were strongly reduced in DARPP-32 knockout mice, indicating a critical role for this phosphoprotein in the antidepressant actions of fluoxetine. Mice chronically treated with fluoxetine had increased levels of DARPP-32 mRNA and protein and a decreased ability to increase phospho-Ser-137-DARPP-32 and phospho-Ser-831-GluR1. These chronic changes may be relevant to the delayed onset of therapeutic efficacy of fluoxetine.A gents that enhance serotonergic neurotransmission, such as serotonin reuptake inhibitors (e.g., fluoxetine), and monoamine oxidase inhibitors (e.g., moclobemide), are effective as antidepressants. Although these agents immediately increase the synaptic availability of serotonin, there is a temporal delay in the onset of their beneficial actions. Recent studies in experimental animals have focused on understanding the effects of various antidepressant agents on signal transduction pathways in neurons located in brain regions thought to be implicated in depression (1, 2). In particular, it has been shown that treatment with various antidepressants, including fluoxetine, enhances the efficacy of the cAMP-dependent protein kinase A (PKA) pathway at several different levels in the frontal cortex and hippocampus (1). The possibility that the cAMP͞PKA system is involved in the action(s) of antidepressants is strongly supported by evidence from basic and clinical studies showing that cAMP phosphodiesterase inhibitors, such as rolipram, have antidepressant efficacy (3, 4).One major target protein for the cAMP͞PKA pathway is dopamine-and cAMP-regulated phosphoprotein of M r 32,000 ref. 5). DARPP-32 is enriched in striatum and the olfactory tubercle (6). Moderate to high levels of DARPP-32 also are found in several extrastriatal regions, such as cerebral cortex, hippocampu...