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)

Previous studies have identified several neuroadaptations to chronic drug use, but relatively few have been functionally linked to addiction-related changes in drug-taking and -seeking behaviors. This article summarizes our past and present studies on the contribution of drug-induced neuroadaptations in the mesolimbic dopamine system to addiction-related changes in drug self-administration and the propensity for relapse in drug withdrawal. Our studies suggest that drug-induced up-regulation in cyclic AMP (cAMP)-protein kinase A (PKA) signaling in the nucleus accumbens (NAc) contributes to escalating drug intake and a propensity for relapse by differentially altering the sensitivity of D1 and D2 dopamine receptors that regulate drug-taking and -seeking behaviors. In addition, our studies suggest that drug-induced neuroplasticity at excitatory synapses in both the ventral tegmental area (VTA) and the NAc also facilitates drug-seeking behavior and the propensity for relapse. Finally, the role of both transient and enduring neuroadaptations in regulating drug-seeking behavior is discussed in view of different learning- and memory-based interactions.
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PMID:Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system. 1546 41

Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson's disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.
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PMID:L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons. 1553 Jun 53

cAMP-dependent protein kinase A (PKA) signaling has a key role in memory processes and has been identified as a potential therapeutic target for memory disorders. The activation of PKA signaling is crucial for the consolidation of long-term memories dependent on the hippocampus and/or the amygdala, By contrast, initial studies indicate that cAMP-PKA activation might impair the working memory and executive functions of the prefrontal cortex. Furthermore, PKA activation in the nucleus accumbens might increase sensitivity to addiction. These complexities must be heeded when designing medications aimed at altering PKA activity. PKA might be most practical as a therapeutic target in disorders with global alterations in cAMP-PKA activity due to genetic or environmental factors.
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PMID:Protein kinase A as a therapeutic target for memory disorders: rationale and challenges. 1576 Jul 70

Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.
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PMID:Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. 1600 Oct 50

Addiction is believed to involve glutamate-dependent forms of synaptic plasticity that promote the formation of new habits focused on drug seeking. We used primary cultures of rat prefrontal cortex (PFC) neurons to explore mechanisms by which dopamine-releasing psychomotor stimulants such as cocaine and amphetamine influence synaptic plasticity, focusing on AMPA receptor trafficking because of its key role in long-term potentiation (LTP). Brief stimulation of D1 dopamine receptors increased surface expression of glutamate receptor 1 (GluR1)-containing AMPA receptors through a protein kinase A-dependent mechanism, by increasing their rate of externalization at extrasynaptic sites. Newly externalized GluR1 remained extrasynaptic under basal conditions but could be translocated into synapses by subsequent NMDA receptor activation. These results suggest that D1 receptors may facilitate LTP by increasing the AMPA receptor pool available for synaptic insertion. However, stimulation of D2 receptors decreased surface and synaptic GluR1 expression. These findings are discussed in the context of evidence that D1 and D2 receptors act independently rather than antagonistically in the intact PFC. D1 receptor facilitation of AMPA receptor synaptic insertion helps explain D1 receptor-dependent facilitation of LTP and learning in the normal brain. Abnormal engagement of this mechanism during unregulated dopamine release may account for maladaptive plasticity after repeated exposure to cocaine or amphetamine.
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PMID:Dopamine receptor stimulation modulates AMPA receptor synaptic insertion in prefrontal cortex neurons. 1609 84

Drug-induced neuroadaptations within the nucleus accumbens, including activation of cAMP-dependent protein kinase A (PKA), may contribute to the synaptic plasticity and behavioural changes that underlie drug addiction. As a direct test of this hypothesis, we examined the effects in rats of PKA activation (Sp-cAMPS infusions of 10 and 20 nmol/side) and inhibition (Rp-cAMPS infusions of 10 and 20 nmol/side) in the nucleus accumbens on motivation to obtain cocaine as measured by responding under the progressive-ratio schedule. Bilateral infusions of Sp-cAMPS (20 nmol/side) resulted in an increase in progressive-ratio responding for cocaine and this effect persisted for several days. In contrast, Rp-cAMPS (20 nmol/side) produced persistent decreases in progressive-ratio responding for cocaine beginning on the day of administration and lasting for several days. These data suggest that alternations in PKA activity within the nucleus accumbens as a consequence of repeated cocaine exposure may contribute to addiction by producing persistent increases in motivation to obtain cocaine.
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PMID:Persistent changes in motivation to self-administer cocaine following modulation of cyclic AMP-dependent protein kinase A (PKA) activity in the nucleus accumbens. 1617 64

Calcium/calmodulin dependent protein kinase II (CaMKII) has been shown to play an important role in the generation and maintenance of opioid tolerance. In this study, trifluoperazine was studied for its effect on morphine tolerance in mice. Acute treatment with trifluoperazine (0.5 mg/kg, i.p.) completely reversed the established antinociceptive tolerance to morphine. Pretreatment with trifluoperazine also significantly attenuated the development of antinociceptive tolerance (p<0.01). Morphine induced a significant up-regulation of supraspinal and spinal CaMKII activity in tolerant mice, which was abolished after the pretreatment or acute treatment with trifluoperazine. These data suggested that trifluoperazine was capable of suppressing opioid tolerance, possibly by the mechanism of inhibiting CaMKII. Since trifluoperazine has been safely used as an antipsychotic drug, we propose that the drug should be studied in humans for the prevention and treatment of opioid tolerance and addiction.
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PMID:Trifluoperazine, an orally available clinically used drug, disrupts opioid antinociceptive tolerance. 1638 Feb 9

The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.
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PMID:Knockout of ERK1 enhances cocaine-evoked immediate early gene expression and behavioral plasticity. 1640 94

Relapse is the most serious limitation of effective medical treatment of opiate addiction. Opiate-related behaviors appear to be modulated by cannabinoid CB1 receptors (CB1) through poorly understood cross-talk mechanisms. Opiate and CB1 receptors are coexpressed in the nucleus accumbens (NAc) and dorsal striatum. These regions also have the highest density of adenosine A2a receptors (A2a) in the brain. We have been investigating the postsynaptic signaling mechanisms of mu-opiate receptors (MORs) and CB1 receptors in primary NAc/striatal neurons. In this article, we present evidence that MOR and CB1 act synergistically on cAMP/PKA signaling in NAc/striatal neurons. In addition, we find that synergy requires adenosine and A2a. Importantly, an A2a antagonist administered either directly into the NAc or indirectly by i.p. injection eliminates heroin-induced reinstatement in rats trained to self-administer heroin, a model of human craving and relapse. These findings suggest that A2a antagonists might be effective therapeutic agents in the management of abstinent heroin addicts.
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PMID:Adenosine A2a blockade prevents synergy between mu-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats. 1668 76

Considerable evidence indicates that neuroadaptations leading to addiction involve the same cellular processes that enable learning and memory, such as long-term potentiation (LTP), and that psychostimulants influence LTP through dopamine (DA)-dependent mechanisms. In hippocampal CA1 pyramidal neurons, LTP involves insertion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors into excitatory synapses. We used dissociated cultures to test the hypothesis that D1 family DA receptors influence synaptic plasticity in hippocampal neurons by modulating AMPA receptor trafficking. Brief exposure (5 min) to a D1 agonist increased surface expression of glutamate receptor (GluR)1-containing AMPA receptors by increasing their rate of externalization at extrasynaptic sites. This required the secretory pathway but not protein synthesis, and was mediated mainly by protein kinase A (PKA) with a smaller contribution from Ca2+-calmodulin-dependent protein kinase II (CaMKII). Prior D1 receptor stimulation facilitated synaptic insertion of GluR1 in response to subsequent stimulation of synaptic NMDA receptors with glycine. Our results support a model for synaptic GluR1 incorporation in which PKA is required for initial insertion into the extrasynaptic membrane whereas CaMKII mediates translocation into the synapse. By increasing the size of the extrasynaptic GluR1 pool, D1 receptors may promote LTP. Psychostimulants may usurp this mechanism, leading to inappropriate plasticity that contributes to addiction-related behaviors.
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PMID:Activation of D1 dopamine receptors increases surface expression of AMPA receptors and facilitates their synaptic incorporation in cultured hippocampal neurons. 1680 Aug 48


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