Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Addiction has long been thought to include both metabolic and psychological dependence. Psychological dependence must involve long-term memory of behavioral patterns in response to specific experimental contexts. Mammalian memory, and more specifically, human memory, is largely associative. Animal models of associative memory have been provided by Pavlovian conditioning of the snail Hermissenda crassicornis and the rabbit. Striking parallels have been observed in the intrinsic molecular and biophysical transformations which accompany acquisition of the conditioned response in these different animals. In brief, associated stimuli cause elevation of Ca2+ and diacylglycerol, translocation of protein kinase C, phosphorylation of a membrane-associated G-protein, reduction of K+ currents, modification of axonal transport and structural alterations of neuronal branches. These changes can be understood and modelled as a plausible basis for memory acquisition during conditioning as well as more cognitively relevant learning such as spatial maze learning for which related neuronal alterations have recently been found. Identification of memory-specific molecular steps may help target pharmacologic agents for amelioration of learned aspects of psychiatric syndromes such as those of drug dependence.
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PMID:Molecular mechanisms of memory and drug dependence. 184 61

The World Health Organization (WHO) developed practical guidelines for pain relief in cancer patients in 1986. Although morphine is a standard opioid analgesic with sufficient analgesic potency, it also has undesirable effects such as drug dependence. Considering the significant of the management of patients with chronic cancer pain, it is no exaggeration to say that the investigation of morphine dependence is now most required research for pain relief. Various studies provide arguments to support substantial roles for mu-opioid receptors associated with the mesolimbic dopaminergic pathway and the possible involvement of delta-opioid receptors in the rewarding effect by morphine in animals. By contrast, the activation of kappa-opioid receptors leads to the suppression of this effect of morphine. It is noteworthy that chronic inflammatory nociception enhances endogenous kappa-opioidergic system, leading to the suppression of rewarding effects of morphine. These results obtained from the basic research strongly reflect the clinical results that psychological dependence on morphine is not a major concern when morphine is used to control pain for cancer patients. Another limiting factor in the clinical utilization of opioids is that repeated administration leads to the development of tolerance to opioids. At the cellular level, phosphorylation of opioid receptors by protein kinases, especially G-protein-coupled receptor kinase (GRK) and protein kinase C (PKC), is likely to play a major role in these tolerant and dependent states. We recently found that repeated administration of mu-agonist causes a down regulation of mu-receptor-mediated G-protein activation, which is associated with a specific upregulation of PKC gamma isoform. We therefore propose that PKC gamma may play a critical role in the development of morphine tolerance.
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PMID:[A new turn of research for morphine dependence]. 1114 49

Ca2+/cAMP response element binding protein (CREB) is an important factor linking the opioid-regulated secondary messenger systems to alterations in gene expression. Opioids regulate CREB level, its phosphorylation and binding to its corresponding response element in the promoters of several genes implicated in drug addiction. CREB mediates the action of opioids on the expression of several genes in brain regions responsible for drug-seeking behavior and manifestation of signs of dependence. Moreover, alterations in CREB level can effect the rewarding properties of morphine and regulate the self-administration of cocaine. At the cellular level CREB acts as convergence point for different cellular pathways. Opioids affect two different intracellular mediator systems: inhibitory--connected with cAMP, and stimulatory--involving calcium and the PKC pathway. Both can affect CREB but in different phases of opiate action. The presence of this biphasic mechanism can explain the phenomenon of the induction of some CRE-controlled genes after both acute and chronic morphine administration. Cellular studies also highlight the relevance of other ATF/CREB family members which can affect Ca2+/cAMP response element (CRE) controlled transcription as well as other transcription factors which make the opioid induction longer lasting.
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PMID:Effect of opioids on Ca2+/cAMP responsive element binding protein. 1120 Jan 84

Prolonged opioid exposure occurs frequently as a result of clinical use or drug abuse. Research using different ligands, cell lines, and animal models in the past three decades has elucidated some correlation between the biochemical events and behavioral changes resulting from opioid tolerance, dependence and addiction. For the most part, opioid tolerance and dependence are associated with up-regulation of the cAMP pathway, mediated by the supersensitization of adenylyl cyclase and by the altered coupling of opioid receptors to stimulatory G proteins. Neuroadaptive changes in signal transduction following prolonged opioid exposure are mediated by protein kinase systems, such as protein kinase C (PKC), cyclic AMP-dependent protein kinase (PKA), Ca2+/camodulin-dependent protein kinase II (CaMKII), G protein-coupled receptor kinases (GRKs) and mitogen-activated protein kinases (MAPKs). Intermediate steps between opioid receptor activation and the second- or third-messenger cascades include GRK-mediated receptor endocytosis and intracellular trafficking, as well as interactions with excitatory amino acid receptors and regulation of nitric oxide synthesis. Thus, prolonged occupancy by opioid receptor agonists can have differential effects on opioid receptor internalization, down-regulation and desensitization, and in the supersensitization of adenylyl cyclase, which contribute to the development of opioid tolerance and dependence. We discuss the role of various protein kinases in the signaling mechanisms underlying these differences. Clearer understanding of the molecular mechanisms of opioid tolerance and dependence will help in the treatment of patients suffering from acute and chronic pain, or drug dependence and addiction.
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PMID:Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence. 1175 Sep 24

Stress increases addictive behaviors and is a common cause of relapse. Corticotropin-releasing factor (CRF) plays a key role in the modulation of drug taking by stress. However, the mechanism by which CRF modulates neuronal activity in circuits involved in drug addiction is poorly understood. Here we show that CRF induces a potentiation of NMDAR (N-methyl-D-aspartate receptor)-mediated synaptic transmission in dopamine neurons of the ventral tegmental area (VTA). This effect involves CRF receptor 2 (CRF-R2) and activation of the phospholipase C (PLC)-protein kinase C (PKC) pathway. We also find that this potentiation requires CRF binding protein (CRF-BP). Accordingly, CRF-like peptides, which do not bind the CRF-BP with high affinity, do not potentiate NMDARs. These results provide evidence of the first specific roles for CRF-R2 and CRF-BP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for both drugs of abuse and stress.
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PMID:Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons. 1289 12

Protein kinase C (PKC) has long been recognized an important family of enzymes that regulate numerous aspects of neuronal signal transduction, neurotransmitter synthesis, release and reuptake, receptor and ion channel function, neuronal excitability, development, and gene expression. Much evidence has implicated PKCs in the effects of several drugs of abuse, and in behavioral responses to these drugs. The present review summarizes the effects of both acute and chronic exposure to various drugs of abuse on individual PKC isozymes in the brain. In addition, we summarize recent studies utilizing mice with targeted deletions of the genes for PKCgamma and PKCepsilon. These studies suggest that individual PKC isozymes play a role in the development of drug dependence and addiction.
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PMID:Protein kinase C isozymes and addiction. 1512 82

Drug dependence is characterized by symptoms causing uncontrollable use of a drug despite its negative consequences. Dependence occurs only in a small fraction of individuals who try an addictive drug, and there is a large variance in individual susceptibility to dependence. Individuals susceptible to dependence exhibit specific comorbid behavioral traits, such as sensation seeking, novelty seeking, and antisocial personality. Studies using genetically engineered mice have delineated the extent to which various genes contribute to both dependence susceptibility and comorbid behavioral traits. Evidence suggests that the genes for dopamine D4 receptor, phosphodiesterease1B, the AMPA receptor subunit GluR1, 5HT1B receptor, protein kinase C and the transcription factor FosB contribute to both dependence susceptibility and comorbid behavioral traits. However, MAO-B influences a behavioral response to novelty without affecting nicotine dependence susceptibility. The mechanisms by which genes influence dependence susceptibility and comorbid behavioral traits are likely to be complex.
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PMID:[Genetic basis of drug dependence and comorbid behavioral traits]. 1529 Dec 43

The present study investigated the effect of the medicinal plant Salviae miltiorrhizae radix (SMR) on dopaminergic neurotransmission in comparison with amphetamine. The effect of SM (0.1 g/ml) on K(+) (20 mM)-stimulated dopamine (DA) release from rat striatal slices was compared with amphetamine (10(-4) M). Amphetamine and SMR significantly increased K(+)-stimulated DA release (P<0.001) from rat striatal slices when compared with K(+)-stimulated alone. On the other hand, to examine whether in vitro SMR treatment induces DA release in PC12 cells, the role of protein kinases has been investigated in the induction of the SMR-mediated events by using inhibitors of protein kinase C (PKC), mitogen activated protein kinase (MAP kinase) or protein kinase A (PKA). PKC inhibitors chelerythrine (50 and 100 nM), Ro31-8220 (100 nM) and the MAP kinase inhibitor, PD98059 (20 microM) inhibited the ability of SMR to elicit the SMR-stimulated DA release. The direct-acting PKC activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA, 100 nM) mimicked the ability of SMR to elicit DA release. On the contrary, a selective PKA inhibitor, 50 microM Rp-8-Br-cAMP, blocked the development of SMR-stimulated DA release. The results demonstrated that SMR may stimulate DA release and that SMR-induced increases in MAP kinase and PKC are important for induction of the enhancement in transporter-mediated DA release and PKA was also required for the enhancement in SMR-stimulated DA release. SMR treatment (0.1-10 microg/ml) to the hydrogen peroxide (H(2)O(2))-treated PC12 cells activated the enzyme activities such as catalase, superoxide dismutase and glutathione peroxidase, and decreased the malondialdehyde level, indicating that SMR has also protective effects against free radical-induced cell toxicity. Therefore, the mechanism by which SMR induces the enhancement in SMR-stimulated DA release is apparent. It remains to be determined whether the effect of SMR on DA function is important in its therapeutic use in the treatment of drug addiction.
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PMID:Salviae Miltiorrhizae BGE Radix increases rat striatal K(+)-stimulated dopamine release and activates the dopamine release with protection against hydrogen peroxide-induced injury in rat pheochromocytoma PC12 cells. 1700 10

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed protein serine/threonine kinase essential for brain development and implicated in synaptic plasticity, dopaminergic neurotransmission, drug addiction, and neurodegenerative disorders. Relatively little is known about the molecular mechanisms that regulate the activity of Cdk5 in vivo. In order to determine whether protein kinase C (PKC) regulates Cdk5 activity in the central nervous system, the phosphorylation levels of two Cdk5 substrates were evaluated under conditions of altered PKC activity in vivo. Treatment of acute striatal slices with a PKC-activating phorbol ester caused a time- and dose-dependent decrease in the levels of phospho-Ser6 inhibitor-1, phospho-Ser67 inhibitor-1, and phospho-Thr75 dopamine- and cAMP-regulated phosphoprotein, Mr 32,000 (DARPP-32). This effect was reversed by the PKC inhibitor, Ro-32-0432. Moreover, phospho-Ser6 inhibitor-1, phospho-Ser67 inhibitor-1, and phospho-Thr75 DARPP-32 levels were elevated in brain tissue from mice lacking the gene for PKC-alpha. PKC did not phosphorylate Cdk5 or its cofactor, p25, in vitro. Striatal levels of the Cdk5 cofactor, p35, did not change in response to phorbol ester treatment. Furthermore, Cdk5 immunoprecipitated from striatal slices treated with phorbol ester had unaltered activity toward a control substrate in vitro. These results suggest that PKC exerts its effects on the phosphorylation state of Cdk5 substrates through an indirect mechanism that may involve the regulatory binding partners of Cdk5 other than its neuronal cofactors.
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PMID:Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C. 1819 Sep 9

The corticotropin-releasing factor (CRF) peptides CRF and uro-cortins 1 to 3 are crucial regulators of mammalian stress and inflammatory responses, and they are also implicated in disorders such as anxiety, depression, and drug addiction. There is considerable interest in the physiological mechanisms by which CRF receptors mediate their widespread effects, and here we report that the native CRF receptor 1 (CRFR1) endogenous to the human embryonic kidney 293 cells can functionally couple to mammalian Ca(V)3.2 T-type calcium channels. Activation of CRFR1 by either CRF or urocortin (UCN) 1 reversibly inhibits Ca(V)3.2 currents (IC(50) of approximately 30 nM), but it does not affect Ca(V)3.1 or Ca(V)3.3 channels. Blockade of CRFR1 by the antagonist astressin abolished the inhibition of Ca(V)3.2 channels. The CRFR1-dependent inhibition of Ca(V)3.2 channels was independent of the activities of phospholipase C, tyrosine kinases, Ca(2+)/calmodulin-dependent protein kinase II, protein kinase C, and other kinase pathways, but it was dependent upon a cholera toxin-sensitive G protein-mediated mechanism relying upon G protein betagamma subunits (Gbetagamma). The inhibition of Ca(V)3.2 channels via the activation of CRFR1 was due to a hyperpolarized shift in their steady-state inactivation, and it was reversible upon washout of the agonists. Given that UCN affect multiple aspects of cardiac and neuronal physiology and that Ca(V)3.2 channels are widespread throughout the cardiovascular and nervous systems, the results point to a novel and functionally relevant CRFR1-Ca(V)3.2 T-type calcium channel signaling pathway.
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PMID:Activation of corticotropin-releasing factor receptor 1 selectively inhibits CaV3.2 T-type calcium channels. 1832 84


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