Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DARPP-32 is a dual-function protein kinase/phosphatase inhibitor that is involved in striatal signaling. The phosphorylation of DARPP-32 at threonine 34 is essential for mediating the effects of both psychostimulant and antipsychotic drugs; however, these drugs are known to have opposing behavioral and clinical effects. We hypothesized that these drugs exert differential effects on striatonigral and striatopallidal neurons, which comprise distinct output pathways of the basal ganglia. To directly test this idea, we developed bacterial artificial chromosome transgenic mice that allowed the analysis of DARPP-32 phosphorylation selectively in striatonigral and striatopallidal neurons. Using this new methodology, we found that cocaine, a psychostimulant, and haloperidol, a sedation-producing antipsychotic, exert differential effects on DARPP-32 phosphorylation in the two neuronal populations that can explain their opposing behavioral effects. Furthermore, we found that a variety of drugs that target the striatum have cell type-specific effects that previous methods were not able to discern.
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PMID:Cell type-specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs. 1862 1

MSA is a neurodegenerative disease and GCIs are specific pathological hallmarks in the brain of MSA patients. Recently, Cdk5 immunopositive GCIs were reported, but the function of Cdk5 in the adult human brain is not clear. Cdk5 has several substrates such as neurofilament and tau proteins. Among these substrates, tau and MAP 1B are immunopositive in GCIs. DARPP32 has been identified as a target for dopamine and PKA in the striatum. DARPP32 has multiple phosphorylation sites, and Cdk5 can phosphorylate DARPP32 at Thr75. The phosphorylation ofThr75 converts DARPP32 into an inhibitor of PKA. DARPP32 is also one of the major substrates of Cdk5, and DARPP32 is widely expressed in both neurons and glial cells. In this study, we determined the immunohistochemical localization of DARPP32 in the brains of a normal control group and patients with MSA. An anti-DARPP32 antibody revealed immunopositive oligodendrocytes and astrocytes widely distributed in the brains of the normal control group and the brain of patients with MSA. Neurons in the caudate, globus pallidus, substantia nigra, hypothalamus, neocortex layers II and III, and cerebellar Purkinje cells were all immunopositive for DARPP32 in the normal control brains, and the immunostaining patterns were very similar to those observed in patients with MSA. We found that DARPP32 was immunopositive in GCIs, and the localization of DARPP32 and Cdk5 was very similar in GCIs. We suggest that Cdk5 and its substrate DARPP32 may be involved in the formation of GCIs through the phosphorylation of DARPP32 in the oligodendrocytes of brains with MSA.
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PMID:Anti-DARPP32 antibody-immunopositive inclusions in the brain of patients with multiple system atrophy. 1880 62

Dopamine D(1)-like receptors play a key role in dopaminergic signaling. In addition to G(s/olf)/adenylyl cyclase (AC)-coupled D(1) receptors, the presence of D(1)-like receptors coupled to G(q)/phospholipase C (PLC) has been proposed. Benzazepine D(1) receptor agonists are known to differentially activate G(s/olf)/AC and G(q)/PLC signaling. By utilizing SKF83959 and SKF83822, we investigated the D(1)-like receptor signaling cascades, which regulate DARPP-32 phosphorylation at Thr34 (the PKA-site) in mouse neostriatal slices. Treatment with SKF83959 or SKF83822 increased DARPP-32 phosphorylation. The SKF83959- and SKF83822-induced increase in DARPP-32 phosphorylation was largely, but partially, antagonized by a D(1) receptor antagonist, SCH23390, and the residual SCH23390-insensitive increase was abolished by an adenosine A(2A) receptor antagonist. In addition, the SKF83959-induced, SCH23390-sensitive increase in DARPP-32 phosphorylation was enhanced by a PLC inhibitor. Analysis in slices from D(1)R/D(2)R-DARPP-32 mice revealed that both D(1) receptor agonists regulate DARPP-32 phosphorylation in striatonigral, but not in striatopallidal, neurons. Thus, dopamine D(1)-like receptors are coupled to three signaling cascades in striatonigral neurons: (i) SCH23390-sensitive G(s/olf)/AC/PKA, (ii) adenosine A(2A) receptor-dependent G(s/olf)/AC/PKA, and (iii) G(q)/PLC signaling. Interestingly, G(q)/PLC signaling interacts with SCH23390-sensitive G(s/olf)/AC/PKA signaling, resulting in its inhibition. Three signaling cascades activated by D(1)-like receptors likely play a distinct role in dopaminergic regulation of psychomotor functions.
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PMID:Regulation of DARPP-32 phosphorylation by three distinct dopamine D1-like receptor signaling pathways in the neostriatum. 1882 71

Phosphodiesterase (PDE) is a critical regulator of cAMP/protein kinase A (PKA) signaling in cells. Multiple PDEs with different substrate specificities and subcellular localization are expressed in neurons. Dopamine plays a central role in the regulation of motor and cognitive functions. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade, and therefore controlled by PDE activity. We used in vitro and in vivo biochemical techniques to dissect the roles of PDE4 and PDE10A in dopaminergic neurotransmission in mouse striatum by monitoring the ability of selective PDE inhibitors to regulate phosphorylation of presynaptic [e.g., tyrosine hydroxylase (TH)] and postsynaptic [e.g., dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32)] PKA substrates. The PDE4 inhibitor, rolipram, induced a large increase in TH Ser40 phosphorylation at dopaminergic terminals that was associated with a commensurate increase in dopamine synthesis and turnover in striatum in vivo. Rolipram induced a small increase in DARPP-32 Thr34 phosphorylation preferentially in striatopallidal neurons by activating adenosine A(2A) receptor signaling in striatum. In contrast, the PDE10A inhibitor, papaverine, had no effect on TH phosphorylation or dopamine turnover, but instead robustly increased DARPP-32 Thr34 and GluR1 Ser845 phosphorylation in striatal neurons. Inhibition of PDE10A by papaverine activated cAMP/PKA signaling in both striatonigral and striatopallidal neurons, resulting in potentiation of dopamine D(1) receptor signaling and inhibition of dopamine D(2) receptor signaling. These biochemical results are supported by immunohistochemical data demonstrating differential localization of PDE10A and PDE4 in striatum. These data underscore the importance of individual brain-enriched cyclic-nucleotide PDE isoforms as therapeutic targets for neuropsychiatric and neurodegenerative disorders affecting dopamine neurotransmission.
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PMID:Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. 1892 23

CK1 constitutes a protein kinase subfamily that is involved in many important physiological processes. However, there is limited knowledge about mechanisms that regulate their activity. Isoforms CK1delta and CK1epsilon were previously shown to autophosphorylate carboxy-terminal sites, a process which effectively inhibits their catalytic activity. Mass spectrometry of CK1alpha and splice variant CK1alphaL has identified the autophosphorylation of the last four carboxyl-end serines and threonines and also for CK1alphaS, the same four residues plus threonine-327 and serine-332 of the S insert. Autophosphorylation occurs while the recombinant proteins are expressed in Escherichia coli. Mutation of four carboxy-terminal phosphorylation sites of CK1alpha to alanine demonstrates that these residues are the principal but not unique sites of autophosphorylation. Treatment of autophosphorylated CK1alpha and CK1alphaS with lambda phosphatase causes an activation of 80-100% and 300%, respectively. Similar treatment fails to stimulate the CK1alpha mutants lacking autophosphorylation sites. Incubation of dephosphorylated enzymes with ATP to allow renewed autophosphorylation causes significant inhibition of CK1alpha and CK1alphaS. The substrate for these studies was a synthetic canonical peptide for CK1 (RRKDLHDDEEDEAMS*ITA). The stimulation of activity seen upon dephosphorylation of CK1alpha and CK1alphaS was also observed using the known CK1 protein substrates DARPP-32, beta-catenin, and CK2beta, which have different CK1 recognition sequences. Autophosphorylation effects on CK1alpha activity are not due to changes in Km(app) for ATP or for peptide substrate but rather to the catalytic efficiency per pmol of enzyme. This work demonstrates that CK1alpha and its splice variants can be regulated by their autophosphorylation status.
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PMID:Autophosphorylation of carboxy-terminal residues inhibits the activity of protein kinase CK1alpha. 1911 51

The antipsychotic agent haloperidol regulates gene transcription in striatal medium spiny neurons (MSNs) by blocking dopamine D2 receptors (D2Rs). We examined the mechanisms by which haloperidol increases the phosphorylation of histone H3, a key step in the nucleosomal response. Using bacterial artificial chromosome (BAC)-transgenic mice that express EGFP under the control of the promoter of the dopamine D1 receptor (D1R) or the D2R, we found that haloperidol induced a rapid and sustained increase in the phosphorylation of histone H3 in the striatopallidal MSNs of the dorsal striatum, with no change in its acetylation. This effect was mimicked by raclopride, a selective D2R antagonist, and prevented by the blockade of adenosine A2A receptors (A2ARs), or genetic attenuation of the A2AR-associated G protein, Galpha(olf). Mutation of the cAMP-dependent phosphorylation site (Thr34) of the 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32) decreased the haloperidol-induced H3 phosphorylation, supporting the role of cAMP in H3 phosphorylation. Haloperidol also induced extracellular signal-regulated kinase (ERK) phosphorylation in striatopallidal MSNs, but this effect was not implicated in H3 phosphorylation. The levels of mitogen- and stress-activated kinase 1 (MSK1), which has been reported to mediate ERK-induced H3 phosphorylation, were lower in striatopallidal than in striatonigral MSNs. Moreover, haloperidol-induced H3 phosphorylation was unaltered in MSK1-knockout mice. These data indicate that, in striatopallidal MSNs, H3 phosphorylation is controlled by the opposing actions of D2Rs and A2ARs. Thus, blockade of D2Rs promotes histone H3 phosphorylation through the A2AR-mediated activation of Galpha(olf) and inhibition of protein phosphatase-1 (PP-1) through the PKA-dependent phosphorylation of DARPP-32.
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PMID:Histone H3 phosphorylation is under the opposite tonic control of dopamine D2 and adenosine A2A receptors in striatopallidal neurons. 1915 68

Schizophrenia is a debilitating chronic mental disorder characterized by significant lifetime risk and high social costs. Although its etiology remains unknown, many of its symptoms may be mitigated by treatment with antipsychotic drugs (APDs). These compounds, generally classified as first- or second-generation antipsychotics, have complex receptor profiles that may account for short-term clinical response and normalization of acute manifestation of the disease. However, APDs have additional therapeutic properties that may not be directly related to receptor mechanisms, but rather involve neuroadaptive changes in selected brain regions. Indeed the neurodevelopmental origin of schizophrenia suggests that the disease is characterized by neuroanatomical and pathophysiological impairments that, at molecular level, may reflect compromised neuroplasticity; the process by which the brain adapts to changes in a specific environment. Accordingly, it is possible that the long-term clinical efficacy of APDs might result from their ability in modulating systems crucially involved in neuroplasticity and cellular resilience. We have reviewed and discussed the results of several studies investigating the post-receptor mechanisms in the action of APDs. We specifically focused on intracellular signaling cascades (PKA, DARPP-32, MAPK, Akt/GSK-3, beta arrestin-2), neurotrophic factors and the glutamatergic system as important mediators for antipsychotic drug induced-neuroplasticity. Altogether, these data highlight the possibility that post-receptor mechanisms will eventually be promising targets for the development of novel drugs that, through their impact on neuroplasticity, may contribute to the improved treatment of patients diagnosed with schizophrenia.
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PMID:Antipsychotic drug actions on gene modulation and signaling mechanisms. 1954 Aug 75

Morphine sensitization is a model of latent, functionally inducible increase in dopamine D(1) receptor-mediated transmission, which may be unmasked by an external stimulus. Morphine-sensitized rats present dopamine D(1) receptor-dependent stereotypies upon morphine challenge and resilience to unavoidable stress-induced behavioral deficits. This tonic increase in dopamine D(1) dopaminergic transmission is counter-adaptive to an enhanced mu-opioid receptor-dependent signaling in striatal areas. Control and sensitized rats show a similar dopamine and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) phosphorylation pattern in striatal areas. Acute morphine administration induced an early increase and delayed decrease in phospho-threonine (Thr)34 DARPP-32 levels accompanied by a delayed increase in phospho-Thr75 DARPP-32 levels in the nucleus accumbens and caudate-putamen of sensitized rats, while it had no effects in control animals. The administration of a selective dopamine D(1) receptor antagonist (SCH 23390) before morphine challenge prevented the behavioral and neurochemical modifications in sensitized rats. 6-Methyl-2-(phenylethynyl)-pyridine, a selective metabotropic glutamate receptor 5 (mGluR(5)) antagonist, administered 1 h after morphine challenge, prevented the delayed phosphorylation changes, but it had no effect when administered before challenge. Moreover, the DARPP-32 phosphorylation pattern in the caudate-putamen of sensitized rats after unavoidable stress exposure was studied. The stress-induced neurochemical modifications and their sensitivity to receptor antagonists were similar to those observed after acute morphine administration. In conclusion, these results suggest that in the experimental conditions used an increase in dopamine output in striatal areas is followed by a complex neurochemical pattern, in which the initial stimulation of dopamine D(1) receptors triggers a sequence of signaling events that lead to an mGluR(5)-mediated increase in phospho-Thr75 DARPP-32 levels. Since DARPP-32 phosphorylated in Thr75 inhibits cAMP-dependent protein kinase (PKA) activity, the final result is a decrease in the dopamine D(1) receptor-dependent phosphorylation events.
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PMID:Dopamine D1 receptor-dependent modifications in the dopamine and cAMP-regulated phosphoprotein of Mr 32 kDa phosphorylation pattern in striatal areas of morphine-sensitized rats. 1955 64

The majority of human genes undergo alternative splicing, which is frequently altered in response to physiological stimuli. DARPP-32 (dopamine and cAMP regulated phosphoprotein, 32kDa) is a component of PKA-dependent signaling pathways. Here we show that DARPP-32 binds directly to the splicing factor tra2-beta1 (transformer 2). DARPP-32 changes the usage of tra2-beta1 dependent alternative exons in a concentration-dependent manner, suggesting that the DARPP-32:tra2-beta1 interaction is a molecular link between signaling pathways and pre-mRNA processing.
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PMID:DARPP-32 binds to tra2-beta1 and influences alternative splicing. 2007 80

Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.
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PMID:A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity. 2016 76


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