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)

The Nav1.8 sodium channel isoform, expressed in sensory neurons and implicated in pain responses, is known to be upregulated in Xenopus oocytes by agents that activate protein kinase A. In the absence of exogenous modulators, Nav1.8 channels expressed in oocytes exhibited spontaneous downregulation, so that the amplitudes of peak sodium currents at the end of a 30-min recording period were reduced to 58% of those at the outset of recording with no change in the properties of the expressed channels. Perfusion of oocytes with either cyclosporin A or deltamethrin, considered to be diagnostic inhibitors of the protein phosphatase calcineurin, at 10 microM blocked spontaneous downregulation. These results identify endogenous calcineurin as the mediator of Nav1.8 sodium channel downregulation in oocytes. The use of a calcineurin inhibitor such as cyclosporin A provides an effective means of stabilizing the expression of Nav1.8 sodium channels in oocytes for functional and pharmacological studies.
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PMID:Cyclosporin A and deltamethrin block the downregulation of Nav1.8 sodium channels expressed in Xenopus oocytes. 1533 72

Although the PI3K (phosphatidylinositol 3-kinase) pathway typically regulates cell growth and survival, increasing evidence indicates the involvement of this pathway in neural plasticity. It is unknown whether the PI3K pathway can mediate pain hypersensitivity. Intradermal injection of capsaicin and NGF produce heat hyperalgesia by activating their respective TRPV1 (transient receptor potential vanilloid receptor-1) and TrkA receptors on nociceptor sensory nerve terminals. We examined the activation of PI3K in primary sensory DRG neurons by these inflammatory agents and the contribution of PI3K activation to inflammatory pain. We further investigated the correlation between the PI3K and the ERK (extracellular signal-regulated protein kinase) pathway. Capsaicin and NGF induce phosphorylation of the PI3K downstream target AKT (protein kinase B), which is blocked by the PI3K inhibitors LY294002 and wortmannin, indicative of the activation of PI3K by both agents. ERK activation by capsaicin and NGF was also blocked by PI3K inhibitors. Similarly, intradermal capsaicin in rats activated PI3K and ERK in C-fiber DRG neurons and epidermal nerve fibers. Injection of PI3K or MEK (ERK kinase) inhibitors into the hindpaw attenuated capsaicin- and NGF-evoked heat hyperalgesia but did not change basal heat sensitivity. Furthermore, PI3K, but not ERK, inhibition blocked early induction of hyperalgesia. In acutely dissociated DRG neurons, the capsaicin-induced TRPV1 current was strikingly potentiated by NGF, and this potentiation was completely blocked by PI3K inhibitors and primarily suppressed by MEK inhibitors. Therefore, PI3K induces heat hyperalgesia, possibly by regulating TRPV1 activity, in an ERK-dependent manner. The PI3K pathway also appears to play a role that is distinct from ERK by regulating the early onset of inflammatory pain.
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PMID:Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization. 1538 13

Molecular mechanisms underlying C-fiber stimulation-induced ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons and its contribution to central sensitization have been investigated. In adult rat spinal slice preparations, activation of C-fiber primary afferents by a brief exposure of capsaicin produces an eightfold to 10-fold increase in ERK phosphorylation (pERK) in superficial dorsal horn neurons. The pERK induction is reduced by blockade of NMDA, AMPA/kainate, group I metabotropic glutamate receptor, neurokinin-1, and tyrosine receptor kinase receptors. The ERK activation produced by capsaicin is totally suppressed by inhibition of either protein kinase A (PKA) or PKC. PKA or PKC activators either alone or more effectively together induce pERK in superficial dorsal horn neurons. Inhibition of calcium calmodulin-dependent kinase (CaMK) has no effect, but pERK is reduced by inhibition of the tyrosine kinase Src. The induction of cAMP response element binding protein phosphorylation (pCREB) in spinal cord slices in response to C-fiber stimulation is suppressed by preventing ERK activation with the MAP kinase kinase inhibitor 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059) and by PKA, PKC, and CaMK inhibitors. Similar signaling contributes to pERK induction after electrical stimulation of dorsal root C-fibers. Intraplantar injection of capsaicin in an intact animal increases expression of pCREB, c-Fos, and prodynorphin in the superficial dorsal horn, changes that are prevented by intrathecal injection of PD98059. Intrathecal PD98059 also attenuates capsaicin-induced secondary mechanical allodynia, a pain behavior reflecting hypersensitivity of dorsal horn neurons (central sensitization). We postulate that activation of ionotropic and metabotropic receptors by C-fiber nociceptor afferents activates ERK via both PKA and PKC, and that this contributes to central sensitization through post-translational and CREB-mediated transcriptional regulation in dorsal horn neurons.
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PMID:Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. 1538 14

Peripheral glucocorticoid receptors (GRs) play a significant role in the anti-inflammatory effects of glucocorticoids; however, the role of central GRs in nociceptive behaviors after peripheral nerve injury (neuropathic pain behaviors) remains unknown. Here we show that the development of neuropathic pain behaviors (thermal hyperalgesia and mechanical allodynia) induced by chronic constriction nerve injury (CCI) in rats was attenuated by either the GR antagonist RU38486 (4 = 2 > 1 = 0.5 microg) or a GR antisense oligonucleotide administered intrathecally twice daily for postoperative days 1-6. The development of thermal hyperalgesia and mechanical allodynia after CCI also was prevented in adrenalectomized rats, whereas the GR agonist dexamethasone (100 microg/kg) given subcutaneously twice daily for postoperative day 1-6 restored CCI-induced neuropathic pain behaviors in the adrenalectomized rats. Mechanistically, CCI induced a time-dependent and region-specific expression of neuronal GRs primarily within the spinal cord dorsal horn ipsilateral to nerve injury, which showed a time course parallel to that of the development of neuropathic pain behaviors. Moreover, the expression of neuronal GR after CCI was mediated in part through an elevated spinal level of interleukin-6 (IL-6) and protein kinase Cgamma (PKCgamma), because intrathecal treatment with an IL-6 antiserum, a PKC inhibitor (cheryrithrine), or PKCgamma knock-out substantially reduced the expression of neuronal GRs as well as neuropathic pain behaviors after CCI. These findings indicate a central role of neuronal GRs in the mechanisms of neuropathic pain behaviors in rats and suggest a potential role for GR antagonists in clinical management of neuropathic pain.
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PMID:Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats. 1545 33

Calcitonin gene-related peptide (CGRP), acting through CGRP receptors, produces behavioral signs of mechanical hyperalgesia in rats and sensitization of wide dynamic range (WDR) neurons in the spinal cord dorsal horn. Although involvement of CGRP receptors in central sensitization has been confirmed, the second-messenger systems activated by CGRP receptor stimulation and involved in pain transmission are not clear. This study tested whether the hyperalgesia and sensitizing effects of CGRP receptor activation on WDR neurons are mediated by protein kinase A or C (PKA or PKC) signaling. Intrathecal injection of CGRP in rats produced mechanical hyperalgesia, as shown by paw withdrawal threshold tests. CGRP-induced hyperalgesia was attenuated significantly by the CGRP1 receptor antagonist, CGRP8-37. The effect was also attenuated significantly by a PKA inhibitor (H89) or a PKC inhibitor (chelerythrine chloride). Electrophysiological experiments demonstrated that superfusion of the spinal cord with CGRP-induced sensitization of spinal dorsal horn neurons. The CGRP effect could be blocked by CGRP8-37. Either a PKA or PKC inhibitor (H89 or chelerythrine) also attenuated this effect of CGRP. These results are consistent with the hypothesis that CGRP produces hyperalgesia by a direct action on CGRP1 receptors in the spinal cord dorsal horn and suggest that the effects of CGRP are mediated by both PKA and PKC second-messenger pathways.
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PMID:Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization. 1548 24

To investigate whether activation of mitogen-activated protein kinase (MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) in the L4 and L5 dorsal root ganglion (DRG) in the L5 spinal nerve ligation (SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small- to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.
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PMID:Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. 1553 93

To investigate the intracellular signal transduction pathways involved in the pathophysiological mechanisms of neuropathic pain after partial nerve injury, we examined the activation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in the dorsal root ganglion (DRG) in the chronic constriction injury (CCI) model. The CCI induced an increase in the phosphorylation of ERK in predominantly injured medium-sized and large-sized DRG neurons and in satellite glial cells. Treatment with the MAPK kinase 1/2 inhibitor, U0126, suppressed CCI-induced mechanical allodynia and partially reversed the increase in neuropeptide Y (NPY) expression in damaged DRG neurons. In contrast, the CCI induced the activation of p38, mainly in uninjured small-to-medium-diameter DRG neurons and in satellite glial cells. The p38 inhibitor, SB203580, reversed the CCI-induced heat hyperalgesia and also the increase in brain-derived neurotrophic factor (BDNF) expression in intact DRG neurons. On the other hand, the nerve growth factor (NGF)-induced increase in BDNF expression in small-to-medium-diameter neurons was reversed by SB203580, whereas the anti-NGF-induced increase in NPY in medium-sized and large-sized neurons was partially blocked by U0126. Taken together, our results demonstrate that the activation of ERK and p38 and also the changes in NPY and BDNF expression may occur in different populations of DRG neurons after CCI, partially through alterations in the target-derived NGF. These changes in injured and intact primary afferents are likely to have a substantial role in pathological states, and MAPK pathways in nociceptors may be potential targets for the development of novel analgesics.
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PMID:Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats. 1557 42

Previous studies have provided evidence supportive of the clinical importance of widespread pain in patients with chronic fatigue syndrome (CFS): pain severity may account for 26-34% of the variability in the CFS patient's activity limitations and participation restrictions. The etiology of widespread pain in CFS remains to be elucidated, but sensitisation of the central nervous system has been suggested to take part of CFS pathophysiology. It is hypothesised that a nitric oxide (NO)-dependent reduction in inhibitory activity of the central nervous system and consequent central sensitisation accounts for chronic widespread pain in CFS patients. In CFS patients, deregulation of the 2',5'-oligoadenylate synthetase/RNase L pathway is accompanied by activation of the protein kinase R enzyme. Activation of the protein kinase R and subsequent nuclear factor-kappaB activation might account for the increased production of NO, while infectious agents frequently associated with CFS (Coxsackie B virus, Epstein-Barr Virus, Mycoplasma) might initiate or accelerate this process. In addition, the evidence addressing behavioural changes in CFS patients fits the central sensitisation-hypothesis: catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by sensitisation of the central nervous system.
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PMID:Pain in patients with chronic fatigue syndrome: does nitric oxide trigger central sensitisation? 1561 66

Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. We demonstrated that very rapid phosphorylation of p38 mitogen-activated protein kinase occurred in dorsal root ganglion (DRG) neurons that were participating in the transmission of noxious signals. Capsaicin injection induced phosphorylated-p38 (p-p38) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-p38 labeling in the DRG after noxious thermal stimuli and found a stimulus intensity-dependent increase in labeled cell size and the number of activated neurons. Most of these p-p38-immunoreactive (IR) neurons were small- and medium-sized neurons, which coexpressed transient receptor potential ion channel TRPV1 and phosphorylated-extracellular signal-regulated protein kinase. Intrathecal administration of the p38 inhibitor, FR167653, reversed the thermal hyperalgesia produced by the capsaicin injection. Inhibition of p38 activation was confirmed by the decrease in the number of p-p38-IR neurons in the DRG following capsaicin injection. Taken together, these findings suggest that the activation of p38 pathways in primary afferents by noxious stimulation in vivo may be, at least in part, correlated with functional activity, and further, involved in the development of thermal hyperalgesia.
Pain 2005 Jan
PMID:Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia. 1562 64

Toward the goal of defining new pharmacological targets for the treatment of chronic pain conditions, in previous studies we established a model, termed 'hyperalgesic priming,' in which an acute inflammatory stimulus causes a long-lasting latent susceptibility to hyperalgesia induced by subsequent exposures to the inflammatory mediator, prostaglandin E2 (PGE2). Those investigations suggested the hypothesis that priming induces a novel linkage between the PGE2-activated second messenger cascade and the epsilon isoform of protein kinase C (PKCepsilon). In the present study, comparison of dose-response relations for hyperalgesia produced by PGE2, forskolin, 8-Br-cAMP, or the protein kinase A (PKA) catalytic subunit, in primed versus normal animals, demonstrated that priming-induced enhancement of the PGE2-activated second messenger cascade occurs downstream to adenylate cyclase and upstream to PKA. Therefore, PGE2-induced hyperalgesia in the primed animal is enhanced by the recruitment of a novel cAMP/PKCepsilon signaling pathway in addition to the usual cAMP/PKA pathway. These observations suggest that pharmacological disruption of the novel interaction between cAMP and PKCepsilon might provide a route toward the development of highly specific methods to reverse cellular processes that underlie chronic pain states.
Pain 2005 Jan
PMID:Chronic hyperalgesic priming in the rat involves a novel interaction between cAMP and PKCepsilon second messenger pathways. 1562 79


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