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)

Nicotinic acetylcholine receptors (nAChRs) regulate dopaminergic signaling in the striatum by modulating the release of neurotransmitters. We have recently reported that nicotine stimulates the release of dopamine via alpha4beta2(*) nAChRs and/or alpha7 nAChRs, leading to the regulation of DARPP-32 at Thr34, the site involved in regulation of protein phosphatase-1 (PP-1). In this study, we investigated the regulation of DARPP-32 phosphorylation at its other sites, Thr75 [cyclin-dependent kinase-5 (Cdk5) site], Ser97 (CK2 site), and Ser130 (CK1 site), that serve to modulate Thr34 phosphorylation and dephosphorylation. In neostriatal slices, nicotine (100 microM) increased phosphorylation of DARPP-32 at Ser97 and Ser130 at an early time point (30 s) and decreased phosphorylation of DARPP-32 at Thr75 at a late time point (3 min). The increase in Ser97 and Ser130 phosphorylation was mediated through the release of dopamine via activation of alpha4beta2(*) nAChRs and alpha7 nAChRs and the subsequent activation of dopamine D1 and D2 receptors. The decrease in Thr75 phosphorylation was mediated through the release of dopamine via activation of alpha4beta2(*) nAChRs and the subsequent activation of dopamine D1 receptors. These various actions of nicotine on modulatory sites of phosphorylation would be predicted to result in a synergistic increase in the state of phosphorylation of DARPP-32 at Thr34 and thus would contribute to increased dopamine D1 receptor/DARPP-32 Thr34/PP-1 signaling.
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PMID:Nicotine regulates DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) phosphorylation at multiple sites in neostriatal neurons. 1604 Aug 13

Dopamine released from lateral efferent fibers modulates the activity of the auditory nerve, but the signaling mechanism by which this is mediated is not known. The present study investigated the signal transduction pathway for the dopamine D1 receptor in the guinea-pig cochlea. D1 receptor immunolabeling was localized to the spiral ganglia neurons and at the base of the inner hair cells. Western immunoblotting on whole cochlear preparations revealed positive bands for the D1 receptor and for dopamine and the cyclic AMP-regulated phosphoprotein. The amplitude of the compound action potential was enhanced in the presence of the D1 receptor agonist, SKF 38393, an effect that was abolished by H89, a protein kinase A inhibitor. Conversely, SKF 83566, a D1 receptor antagonist decreased the amplitude of compound action potential, while forskolin, a protein kinase A activator prevented this effect. Furthermore, it was found that the level of glutamate receptor 1 phosphorylation at the protein kinase A site (Ser845) was increased by the D1 agonist, but decreased by D1 antagonist. Our results provide evidence that the D1 receptor is localized in the spiral ganglion neurons as well as the nerve endings under the inner hair cells and they can modulate auditory nerve function. One signal transduction pathway of D1 receptor in the auditory nerve is via protein kinase A-mediated glutamate receptor 1 phosphorylation.
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PMID:The signal transduction pathway for the dopamine D1 receptor in the guinea-pig cochlea. 1633 Jan 49

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor activated by a broad range of monoamines and amphetamine-related psychostimulants. Recent studies demonstrated wide distribution of TAAR1 in brain, coexpression of TAAR1 with dopamine transporter (DAT) in a subset of dopamine neurons in both mouse and rhesus monkey substantia nigra, and monoamine transporter-modulated activation. This study explored whether TAAR1 could influence DAT-mediated dopamine uptake and efflux. Rhesus monkey TAAR1 expressed with DAT in human embryonic kidney 293 cells was dose-dependently activated by dopamine or (+)-methamphetamine. This activation resulted in large cAMP increases and a transient reduction in [3H]dopamine accumulation within the cells, which was similar to the effect of dopamine D1 receptor (D1) or forskolin treatment. In addition, TAAR1 effects on dopamine uptake could be blocked by a protein kinase A or protein kinase C (PKC) inhibitor. [3H]Dopamine efflux assays performed in Dulbecco's modified Eagle's medium displayed a TAAR1-dependent spontaneous [3H]dopamine efflux that was dose-dependently augmented by dopamine or (+)-methamphetamine and that was blocked by either methylphenidate or a PKC inhibitor. DAT cells in Krebs-HEPES buffer had an apparent spontaneous [3H]dopamine loss, but it could not be blocked by either methylphenidate or a PKC inhibitor. Taken together, this study provides evidence that TAAR1 is involved in functional regulation of DAT and suggests that TAAR1 is a potentially important target for therapeutics for methamphetamine addiction.
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PMID:Trace amine-associated receptor 1 is a modulator of the dopamine transporter. 1723 99

Activation of the cAMP/PKA pathway in the dopaminoceptive neurons of the striatum has been proposed to mediate the actions of various classes of drugs of abuse. Here, we show that, in the mouse nucleus accumbens and dorsal striatum, acute administration of morphine resulted in an increase in the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34, without affecting phosphorylation at Thr75. The ability of morphine to stimulate Thr34 phosphorylation was prevented by blockade of dopamine D1 receptors. DARPP-32 knockout mice and T34A DARPP-32 mutant mice displayed a lower hyperlocomotor response to a single injection of morphine than wild-type controls. In contrast, in T75A DARPP-32 mutant mice, morphine-induced psychomotor activation was indistinguishable from that of wild-type littermates. In spite of their reduced response to the acute hyperlocomotor effect of morphine, DARPP-32 knockout mice and T34A DARPP-32 mutant mice were able to develop behavioral sensitization to morphine comparable to that of wild-type controls and to display morphine conditioned place preference. These results demonstrate that dopamine D1 receptor-mediated activation of the cAMP/DARPP-32 cascade in striatal medium spiny neurons is involved in the psychomotor action, but not in the rewarding properties, of morphine.
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PMID:Activation of the cAMP/PKA/DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward. 1725 6

CB1 receptor agonists increase the state of phosphorylation of the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at the cAMP-dependent protein kinase site, Thr 34. This effect, which occurs in the medium spiny neurons of the striatum, has been proposed to mediate the motor depressant action of cannabinoids. In this study, we have examined the effect produced by systemic administration of Delta(9)-tetrahydrocannabinol (THC), the major component of marihuana and hashish, on DARPP-32. We show that THC increases DARPP-32 phosphorylation at Thr 34 both in dorsal striatum and nucleus accumbens. Time-course and dose-response experiments indicate that DARPP-32 phosphorylation is maximal 30 min following administration of 10mg/kg of THC. The THC-mediated increase in DARPP-32 phosphorylation is reduced by administration of the CB1 receptor antagonist, SR141716A (3mg/kg). A similar attenuation of the effect of THC is also exerted by suppression of cAMP signaling achieved using the dopamine D1 receptor antagonist, SCH23390 (0.125 mg/kg), or the adenosine A2A receptor antagonist, KW6002 (3mg/kg). These results indicate that, in the striatum, THC promotes PKA-dependent phosphorylation of DARPP-32 in striatal medium spiny neurons expressing dopamine D1 and adenosine A2A receptors.
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PMID:Regulation of DARPP-32 phosphorylation by Delta9-tetrahydrocannabinol. 1768 97

The influence of the mammalian retinal circadian clock on retinal physiology and function is widely recognized, yet the cellular elements and neural regulation of retinal circadian pacemaking remain unclear due to the challenge of long-term culture of adult mammalian retina and the lack of an ideal experimental measure of the retinal circadian clock. In the current study, we developed a protocol for long-term culture of intact mouse retinas, which allows retinal circadian rhythms to be monitored in real time as luminescence rhythms from a PERIOD2::LUCIFERASE (PER2::LUC) clock gene reporter. With this in vitro assay, we studied the characteristics and location within the retina of circadian PER2::LUC rhythms, the influence of major retinal neurotransmitters, and the resetting of the retinal circadian clock by light. Retinal PER2::LUC rhythms were routinely measured from whole-mount retinal explants for 10 d and for up to 30 d. Imaging of vertical retinal slices demonstrated that the rhythmic luminescence signals were concentrated in the inner nuclear layer. Interruption of cell communication via the major neurotransmitter systems of photoreceptors and ganglion cells (melatonin and glutamate) and the inner nuclear layer (dopamine, acetylcholine, GABA, glycine, and glutamate) did not disrupt generation of retinal circadian PER2::LUC rhythms, nor did interruption of intercellular communication through sodium-dependent action potentials or connexin 36 (cx36)-containing gap junctions, indicating that PER2::LUC rhythms generation in the inner nuclear layer is likely cell autonomous. However, dopamine, acting through D1 receptors, and GABA, acting through membrane hyperpolarization and casein kinase, set the phase and amplitude of retinal PER2::LUC rhythms, respectively. Light pulses reset the phase of the in vitro retinal oscillator and dopamine D1 receptor antagonists attenuated these phase shifts. Thus, dopamine and GABA act at the molecular level of PER proteins to play key roles in the organization of the retinal circadian clock.
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PMID:An autonomous circadian clock in the inner mouse retina regulated by dopamine and GABA. 1895 77

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

The intrinsic properties of neurons that enable them to maintain depolarized, persistently activated states in the absence of sustained input are poorly understood. In short-term memory tasks, individual prefrontal cortical (PFC) neurons can maintain persistent action potential output during delay periods between informative cues and behavioral responses. Dopamine and drugs of abuse alter PFC function and working memory, possibly by modulating intrinsic neuronal properties. Here we used patch-clamp recording of layer 5 PFC pyramidal neurons to identify a postsynaptic depolarization that was evoked by action potential bursts and mediated by metabotropic glutamate receptor 5 (mGluR5). This depolarization occurred in the absence of recurrent synaptic activity and was reduced by a dopamine D1 receptor (D1R) protein kinase A pathway. After behavioral sensitization to cocaine, the depolarization was substantially diminished and D1R modulation was lost. We propose that burst-evoked intrinsic depolarization is a form of short-term cellular memory that is modulated by dopamine and cocaine experience.
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PMID:Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. 1916 52

Previous work demonstrates that microinjections of dopamine D1 receptor agonists and antagonists directly into the medial prefrontal cortex (mPFC) of rats can affect attention in the 5-choice serial reaction time task (5CSRTT), a rodent test analogous to the continuous performance task used to study attention in humans. These studies were designed to determine if intra-mPFC modulation of cAMP-dependent protein kinase (PKA), an intracellular target of D1 receptor stimulation, also affects attention. We examined the effects of localized microinfusions of the cAMP analog Sp-cAMPS (to activate PKA) or Rp-cAMPS (to inhibit PKA) in the 5CSRTT. In parallel, we examined the effects of these manipulations on activity levels in an open field, as well as on motivation and the capacity to make complex operant responses using the intracranial self-stimulation (ICSS) test. Inhibition of PKA reduced accuracy in the 5CSRTT and caused substantial increases in locomotor activity without affecting motivation or the capacity to emit operant responses at high rates. Stimulation of PKA also affected some measures of performance in the 5CSRTT, but this effect was associated with reduced capacity to respond at high rates. Viral vector-mediated disruption of cAMP response element-binding protein (CREB), a transcription factor directly activated by PKA, also reduced accuracy in the 5CSRTT, raising the possibility that acute inhibition of PKA and sustained inhibition of CREB affect attention through common mechanisms. These studies indicate that PKA inhibition within the mPFC of rats produces inattention and hyperactivity, and thus might be useful in modeling human attention disorders.
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PMID:Attention deficits and hyperactivity following inhibition of cAMP-dependent protein kinase within the medial prefrontal cortex of rats. 1938 23

Drug addiction represents a pathological form of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. The aberrant behavioral phenotypes can be assessed by an animal model of drug-induced behavioral sensitization, which is characterized by an initiation stage that is formed in the ventral tegmental area and a behavioral expression stage determined mainly in the nucleus accumbens. Numerous studies during past decades demonstrate that the mesocorticolimbic dopamine pathway plays an essential role in the development of behavioral sensitization. Moreover, a series of cellular signaling pathways and gene expression determine the severity of addictive behaviors. In addition to the well-characterized dopamine D1 receptor-mediated cAMP/protein kinase A up-regulation in the nucleus accumbens, recent reports indicate the cellular mediator dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and transcription regulator DeltaFosB are associated with the accumbal PKA pathway to modulate the development of behavioral sensitization. The finding of cAMP-independent and dopamine D2 receptor-mediated Akt/GSK3 in activation in the nucleus accumbens of behaviorally sensitized animals implies that a signal cascade down-stream of both dopamine D1 and D2 receptors comprises the mainstay of the addiction network. This review outlines the cellular pathways that have been demonstrated to participate in psychostimulant addiction, focused particularly in the nucleus accumbens.
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PMID:Molecular mechanisms of psychostimulant addiction. 1940 4


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