Mechanism of Regulation of Casein Kinase I Activity by Group I Metabotropic Glutamate Receptors

Self Cite

133

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.

Section: Discussionmentioning

confidence: 53%

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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133

“…Group I mGlu receptors activate PLC␤ and stimulate the generation of inositol trisphosphate, leading to an increase in intracellular Ca 2ϩ . The increased intracellular Ca 2ϩ activates PP-2B, causing dephosphorylation of inhibitory autophosphorylation sites of CK1 , which results in its activation (11). Cdk5 is subsequently activated by CK1 (10) by an unknown mechanism and stimulates the phosphorylation of DARPP-32 at Thr-75.…”

Section: Regulation Of Darpp-32 Thr-34 Phosphorylation By Glutamate Nmentioning

confidence: 99%

“…Activation of group I mGlu receptors also increases DARPP-32 phosphorylation at Thr-75 as well as Ser-130 [casein kinase-1 (CK1)-site] (10). Group I mGlu receptors stimulate phospholipase C (PLC) and CK1 (11), resulting in activation of Cdk5 by an unknown mechanism, leading to phosphorylation of Thr-75. However, the signal transduction pathways mediating the biological effects of glutamate per se have not received much attention.…”

mentioning

confidence: 99%

Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades

Nishi

Watanabe²,

Higashi³

et al. 2005

Self Cite

120

Dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) plays a central role in medium spiny neurons in the neostriatum in the integration of various neurotransmitter signaling pathways. In its Thr-34-phosphorylated form, it acts as a potent protein phosphatase-1 inhibitor, and, in its Thr-75-phosphorylated form, it acts as a cAMP-dependent kinase inhibitor. Here, we investigated glutamate-dependent signaling cascades in mouse neostriatal slices by analyzing the phosphorylation of DARPP-32 at Thr-34 and Thr-75. Treatment with glutamate (5 mM) caused a complex change in DARPP-32 Thr-34 phosphorylation. An initial rapid increase in Thr-34 phosphorylation was NMDA͞␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)͞metabo-tropic glutamate-5 receptor-dependent and was mediated through activation of a neuronal nitric oxide synthase͞nitric oxide͞cGMP͞ cGMP-dependent kinase signaling cascade. A subsequent decrease in phosphorylation was attributable to activation of an NMDA͞ AMPA receptor͞Ca 2؉ ͞protein phosphatase-2B signaling cascade. This decrease was followed by rephosphorylation via a pathway involving metabotropic glutamate-5 receptor͞phospholipase C and extracellular receptor kinase signaling cascade. Treatment with glutamate initially decreased Thr-75 phosphorylation through activation of NMDA͞AMPA receptor͞Ca 2؉ ͞protein phosphatase-2A signaling. Thereafter, glutamate slowly increased Thr-75 phosphorylation through activation of metabotropic glutamate-1 receptor͞phospholipase C signaling. Our analysis of DARPP-32 phosphorylation in the neostriatum revealed that glutamate activates at least five different signaling cascades with different time dependencies, resulting in complex regulation of protein kinase and protein phosphatase activities.dopamine ͉ striatum ͉ nitric oxide ͉ metabotropic glutamate receptor ͉ protein phosphatase D ARPP-32, a dopamine-and cAMP-regulated phosphoprotein of 32 kDa, is a signal transduction molecule that is selectively enriched in medium spiny neurons in the neostriatum (1). Mice lacking DARPP-32 exhibit profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication (2), indicating an essential role for DARPP-32 in dopamine signaling. DARPP-32 is phosphorylated at Thr-34 by cAMP-dependent protein kinase (PKA), resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is phosphorylated at Thr-75 by cyclin-dependent kinase 5 (Cdk5) (3). DARPP-32 phosphorylated at Thr-75 inhibits PKA activity and thereby reduces the efficacy of dopamine signaling. Dopamine, by means of dopamine D1 receptors, activates PKA, which directly stimulates DARPP-32 Thr-34 phosphorylation and indirectly stimulates DARPP-32 Thr-75 dephosphorylation (4, 5). By regulating the activity of PKA and PP-1, dopamine controls the state of phosphorylation of various intracellular targets.Glutamate is the major excitatory neurotransmitter in the brain. The excitation of medium spiny neurons i...

“…In mammals and vertebrates, there are seven CK1 genes coding for ␣, ␤, ␥1, ␥2, ␥3, ␦, and isoforms (14), and some of these genes generate several proteins through alternative splicing (15). The CK1 isoforms may have different functions; for instance, CK1 is involved in regulating circadian rhythm through phosphoration of period (per) proteins (16), and it has also been linked to the activity of group I metabotropic glutamate receptors (17). CK1␦ may be involved in neurodegenerative diseases (18).…”

Section: Ck1mentioning

confidence: 99%

A noncanonical sequence phosphorylated by casein kinase 1 in β-catenin may play a role in casein kinase 1 targeting of important signaling proteins

Marin

Bustos

Cesaro

et al. 2003

130

115

Protein kinase casein kinase 1 (CK1) phosphorylates Ser-45 of ␤-catenin, ''priming'' the subsequent phosphorylation by glycogen synthase-3 of residues 41, 37, and 33. This concerted phosphorylation of ␤-catenin signals its degradation and prevents its function in triggering cell division. The sequence around Ser-45 does not conform to the canonical consensus for CK1 substrates, which prescribes either phosphoamino acids or acidic residues in position n؊3 from the target serine. However, the ␤-catenin sequence downstream from Ser-45 is very similar to a sequence recognized by CK1 in nuclear factor for activated T cells 4. The common features include an SLS motif followed two to five residues downstream by a cluster of acidic residues. Synthetic peptides reproducing residues 38 -65 of ␤-catenin were assayed with purified rat liver CK1 or recombinant CK1␣ and CK1␣L from zebrafish. The results demonstrate that SLS and acidic cluster motifs are crucial for CK1 recognition. Pro-44 and Pro-52 are also important for efficient phosphorylation. Similar results were obtained with the different isoforms of CK1. Phosphorylation of mutants of full-length recombinant ␤-catenin from zebrafish confirmed the importance of the SLS and acidic cluster motifs. A search for proteins with similar motifs yielded, among other proteins, adenomatous polyposis coli, previously found to be phosphorylated by CK1. There is a strong correlation of ␤-catenin mutations found in thyroid tumors with the motifs recognized by CK1 in this protein.consensus sequence ͉ nuclear factor for activated T cells 4 ͉ adenomatous polyposis coli ͉ Wnt signaling ͉ thyroid tumor mutations