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 development of tolerance to the analgesic effects of morphine as well as morphine dependence were greatly reduced by co-administration with morphine of GM1 ganglioside, a substance reported to block the translocation of protein kinase C (PKC) from cytosol to membrane of neurons. Rats made tolerant to intrathecal administration of morphine showed increased membrane-bound PKC in the superficial layers (laminae I and II) of the spinal cord dorsal horn but not in deeper layers. This increase was prevented by co-administration with morphine of GM1 ganglioside. These results indicate that the translocation and activation of PKC may be a critical step in the development of opiate tolerance and dependence. Modulation of PKC translocation and activation may prove useful for the management of pain and opiate addiction.
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PMID:The development of morphine tolerance and dependence is associated with translocation of protein kinase C. 889 58

With chronic opiate use, opioid receptor desensitization may be one of the important mechanisms underlying the development of opiate tolerance and addiction. Opioid receptors belong to the G protein-coupled receptor superfamily. In this study, the mouse delta-opioid receptor (delta OR) was used in a model system to investigate the role of opioid receptor phosphorylation in receptor desensitization. When expressed in 293 cells and exposed to agonist, the delta OR underwent receptor-specific desensitization within 10 min. This agonist-induced desensitization corresponded temporally to a 3-fold increase in receptor phosphorylation. Phorbol ester, but not forskolin, also stimulated phosphorylation of the delta OR in 293 cells. Although down-regulation of protein kinase C failed to affect agonist-induced receptor phosphorylation, it abolished phorbol ester-induced receptor phosphorylation. Agonist-induced delta OR phosphorylation must therefore involve kinases other than protein kinase C. Whereas overexpression of a dominant negative mutant (K220R) of beta-adrenergic receptor kinase-1 (beta ARK1) in 293 cells significantly reduced agonist-dependent phosphorylation of the delta OR, overexpression of beta ARK1 or G protein-coupled receptor kinase-5 significantly enhanced this phosphorylation. Concordantly, beta ARK1-K220R overexpression reduced agonist-dependent delta OR desensitization, whereas beta ARK1 overexpression enhanced this densensitization. We conclude that short term desensitization of the delta OR involves phosphorylation of the receptor by one or more G protein-coupled receptor kinases.
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PMID:Agonist-dependent phosphorylation of the mouse delta-opioid receptor: involvement of G protein-coupled receptor kinases but not protein kinase C. 765 49

The abundance of protein kinase C-alpha and beta isoforms (PKC-alphabeta), PKC-alpha messenger (m) RNA and guanine nucleotide-binding G protein subunits (G alpha(i1/2), G alpha(o), and G beta) were quantitated in the rat cerebral cortex after acute and chronic treatments with various opiate drugs. Acute (100 mg/kg for 2 h) and chronic (10 to 100 mg/kg for 5 days) treatment with morphine decreased similarly the immunoreactivity of PKC-alphabeta (28% and 32%, respectively). Acute (2 h) and chronic treatment (5 days) with other mu-agonists heroin (30 mg/kg and 10 to 30 mg/kg) and methadone (30 mg/kg and 5 to 30 mg/kg) also induced similar decreases of PKC-alphabeta (acute: 25% and 23%; chronic: 28% and 18%). After the chronic treatments, spontaneous (48 h) or naloxone (2 mg/kg)-precipitated opiate withdrawal (2 h) resulted in up-regulation of PKC-alphabeta above control levels (30-38%), and in the case of morphine withdrawal in a concomitant marked increase in the expression of PKC-alpha mRNA levels (2.3-fold). Acute (2 h) treatments with pentazocine (80 mg/kg, mixed kappa/delta-agonist and mu-antagonist), spiradoline (30 mg/kg, selective kappa-agonist) and [D-Pen2, D-Pen5] enkephalin (14 nmol i.c.v., selective delta-agonist) induced significant decreases of PKC-alphabeta (19-33%). Chronic (5 days) treatment with pentazocine (10 to 80 mg/kg), but not spiradoline (2 to 30 mg/kg), also induced a similar decrease of PKC-alphabeta (35%). In pentazocine- or spiradoline-dependent rats, naloxone (2 mg/kg) did not induce up-regulation of brain PKC-alphabeta. Acute (10 mg/kg for 2 h) and chronic (2x10 mg/kg for 5 and 14 days) treatment with naloxone did not alter PKC-alphabeta immunoreactivity. Chronic, but not acute, treatment with mu-agonists (morphine, heroin and methadone) increased the immunoreactivities of G alpha(i1/2) (33-37%), G alpha(o), (25-41%) and G beta (10-33%) protein subunits. In heroin- and methadone-dependent rats naloxone (2 mg/kg)-precipitated withdrawal (2 h) did not modify the up-regulation of these G proteins induced by chronic mu-opiate treatment. In marked contrast to mu-agonists, chronic treatment with high doses of pentazocine and spiradoline or acute treatment with [D-Pen2, D-Pen5] enkephalin did not result in up-regulation of these G protein subunits. After chronic treatment with mu-agonists, significant negative correlations were found when the percentage changes in immunoreactivity of PKC-alphabeta were related to the percentage changes in immunoreactivity of G alpha(i1/2), (r = -0.53, n = 29) and G beta (r = -0.41, n = 24) in the same brains. PKC-alphabeta abundance did not correlate significantly with the density of G alpha(o) (r = -0.21, n = 28). Together the results indicate that the brain PKC-alphabeta system may play a major regulatory role in opiate tolerance and dependence. Moreover, the possible in vivo cross-communication between this regulatory enzyme and specific inhibitory G proteins may also be of relevance in the cellular and molecular processes of opiate addiction.
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PMID:Modulation of immunoreactive protein kinase C-alpha and beta isoforms and G proteins by acute and chronic treatments with morphine and other opiate drugs in rat brain. 910 66

To assess the status of opioid receptors in the human brain during the process of opiate addiction, the abundance of immunoreactive mu-opioid receptors was quantitated in postmortem brains of chronic opiate addicts who had died of a heroin or methadone overdose. The immunoreactive levels of the associated enzyme protein kinase C (PKC-alpha and zeta isoforms) and G proteins (G alpha(i1/2) subunits) were also assessed in the same brains. In the frontal cortex of opiate addicts, the abundance of mu-opioid receptors was not different from that obtained in matched controls. The level of Ca2+-dependent PKC-alpha was decreased (25%), whereas that of the atypical PKC-zeta remained unchanged. The density of G alpha(i1/2) proteins also was found to be increased (40%). The results indicate that opiate addiction in humans does not appear to be associated with a reduced density of brain mu-opioid receptors. The sustained down-regulation of PKC-alpha in the brain of opiate addicts would allow the up-regulation of G alpha(i1/2) proteins aimed at compensating the postulated desensitization of the mu-opioid receptor system.
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PMID:Regulation of immunolabelled mu-opioid receptors and protein kinase C-alpha and zeta isoforms in the frontal cortex of human opiate addicts. 915 34

Although nicotine has been implicated as a potential factor in the pathogenesis of human lung cancer, its mechanism of action in the development of this cancer remains largely unknown. The present study provides evidence that nicotine (a) activates the mitogen-activated protein (MAP) kinase signalling pathway in lung cancer cells, specifically extracellular signal-regulated kinase (ERK2), resulting in increased expression of the bcl-2 protein and inhibition of apoptosis in these cells; and (b) blocks the inhibition of protein kinase C (PKC) and ERK2 activity in lung cancer cells by anti-cancer agents, such as therapeutic opioid drugs, and thus can adversely affect cancer therapy. Nicotine appears to have no effect on the activities of c-jun NH2-terminal protein kinase (JNK) and p38 MAP kinases, which have also been shown to be involved in apoptosis. While exposure to nicotine can result in the activation of the two major signalling pathways (MAP kinase and PKC) that are known to inhibit apoptosis, nicotine regulation of MAP (ERK2) kinase activity is not dependent on PKC. These effects of nicotine occur at concentrations of 1 microM or less, that are generally found in the blood of smokers, and could lead to disruption of the critical balance between cell death and proliferation, resulting in the unregulated growth of cells. The findings suggest caution in the use of smokeless tobacco products to treat smoking addiction, as they could have a potentially deleterious effect in patients with undetectable early tumour development.
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PMID:Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. 960 Mar 37

1. Receptor for activated C kinase 1 (RACK1) is an intracellular receptor for protein kinase C (PKC) that regulates the cellular enzyme localization. Because opiate drugs modulate the levels of brain PKC (Ventayol et al., 1997), the aim of this study was to assess in parallel the effects of morphine on RACK1 and PKC-alpha and beta isozymes densities in rat brain frontal cortex by immunoblot assays. 2. Acute morphine (30 mg kg(-1), i.p., 2 h) induced significant increases in the densities of RACK1 (33%), PKC-alpha (35%) and PKC-beta (23%). In contrast, chronic morphine (10-100 mg kg(-1), i.p., 5 days) induced a decrease in RACK1 levels (22%), paralleled by decreases in the levels of PKC-alpha (16%) and PKC-beta (16%). 3. Spontaneous (48 h) and naloxone (2 mg kg(-1), i.p., 2 h)-precipitated morphine withdrawal after chronic morphine induced marked up-regulations in the levels of RACK1 (38-41%), PKC-alpha (51-52%) and PKC-beta (48-62%). 4. In the same brains and for all combined treatments, there were significant positive correlations between the density of RACK1 and those of PKC-alpha (r=0.85, n = 35) and PKC-beta (r=0.75, n=32). 5. These data indicate that RACK1 is involved in the short- and long-term effects of morphine and in opiate withdrawal, and that RACK1 modulation by morphine or its withdrawal is parallel to those of PKC-alpha and beta isozymes. Since RACK1 facilitates the PKC substrate accessibility, driving its cellular localization, the coordinate regulation of the PKC/RACK system by morphine could be a relevant molecular mechanism in opiate addiction.
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PMID:Parallel modulation of receptor for activated C kinase 1 and protein kinase C-alpha and beta isoforms in brains of morphine-treated rats. 1038 32

In a study of a possible substrate underlying morphine addiction, we examined NMDA receptor-mediated synaptic transmission of core nucleus accumbens neurons after chronic morphine treatment, using intracellular recording in a slice preparation of rat. We evoked pharmacologically isolated NMDA EPSCs by local stimulation and elicited inward currents by NMDA superfusion. In control slices, Mg(2+) and phorbol 12,13-diacetate (PDAc), a protein kinase C activator, strongly inhibited and increased, respectively, NMDA EPSC amplitudes. The PDAc effects were likely postsynaptic because PDAc enhanced the currents evoked by superfused NMDA to the same extent that it did the NMDA EPSCs. Chronic morphine treatment significantly decreased NMDA EPSC amplitudes and the sensitivity of NMDA EPSCs to Mg(2+) and PDAc, as well as the kinetics of the decay (inactivation rate) of the EPSCs (from 97 +/- 2.5 msec in untreated rats to 78.7 +/- 1.8 msec in slices from treated rats). One week after withdrawal, the Mg(2+) and PDAc effects were still significantly less than those in control slices. Interestingly, 1 week of withdrawal led to an increased NMDA EPSC inactivation rate compared with controls. These data demonstrate that chronic morphine treatment significantly alters NMDA receptor-mediated synaptic transmission in the accumbens, and these effects persist 1 week after withdrawal. These long-term effects may represent an important neuroadaptation in opiate dependence.
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PMID:Chronic morphine treatment alters NMDA receptor-mediated synaptic transmission in the nucleus accumbens. 1051 25

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

Long-term administration of opiates leads to changes in the effects of these drugs, including tolerance, sensitization and physical dependence. There is, as yet, incomplete understanding of the neural mechanisms that underlie these phenomena. Tolerance, sensitization and physical dependence can be considered adaptive processes similar to other experience-dependent changes in the brain, such as learning and neural development. There is considerable evidence demonstrating that N-methyl-D-aspartate (NMDA) receptors and downstream signaling cascades may have an important role in different forms of experience-dependent changes in the brain and behavior. This review will explore evidence indicating that NMDA receptors and downstream messengers may be involved in opiate tolerance, sensitization and physical dependence. This evidence has been used to develop a cellular model of NMDA receptor/opiate interactions. According to this model, mu opioid receptor stimulation leads to a protein kinase C-mediated activation of NMDA receptors. Activation of NMDA receptors leads to influx of calcium and activation of calcium-dependent processes. These calcium-dependent processes have the ability to produce critical changes in opioid-responsive neurons, including inhibition of opioid receptor/second messenger coupling. This model is similar to cellular models of learning and neural development in which NMDA receptors have a central role. Together, the evidence suggests that the mechanisms that underlie changes in the brain and behavior produced by long-term opiate use may be similar to other central nervous system adaptations. The experimental findings and the resulting model may have implications for the treatment of pain and addiction.
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PMID:The neurobiology of opiate tolerance, dependence and sensitization: mechanisms of NMDA receptor-dependent synaptic plasticity. 1282 26


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