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)

Nerve injury elicits both universal and limited responses. Among the former is regenerative growth, which occurs in most peripheral neurons, and among the latter is the long-term hyperexcitability that appears selectively in nociceptive sensory neurons. Since positive injury signals communicate information from the site of an injury to the cell body, we hypothesize that a nerve injury activates both universal and limited positive injury signals. Studies in Aplysia indicate that protein kinase G is a limited signal that is responsible for the induction of long-term hyperexcitability. Given that long-term hyperexcitability contributes to chronic pain after axotomy in rodent neuropathic pain models, we investigated its underlying basis in the rat peripheral nervous system. Using biochemical assays, Western blots, and immunocytochemistry we found that the Type 1alpha protein kinase G is the predominant isoform in the rat periphery. It is present primarily in axons and cell bodies of nociceptive neurons, including populations that are isolectin B4-positive, isolectin B4-negative, and those that express transient receptor potential vanilloid receptor-1. Surprisingly, protein kinase G is not present in the facial nerve, which overwhelmingly contains axons of motor neurons. Crushing the sciatic nerve or a cutaneous sensory nerve activates protein kinase G in axons and results in its retrograde transport to the neuronal somata in the DRG. Preventing the activation of protein kinase G by injecting Rp-8-pCPT-cGMPS into the crush site abolished the transport. The protein kinase A inhibitor Rp-8-pCPT-cAMPS had no effect. Extracellular signal-related kinases 42/44 are also activated and transported after nerve crush, but in both motor and sensory axons. Chronic pain has been linked to long-term hyperexcitability following a nerve inflammation in several rodent models. We therefore injected complete Freund's adjuvant into the hindpaw to induce an inflammation and found that protein kinase G was activated in the sural nerve and transported to the DRG. In contrast, the extracellular signal-related kinases in the sensory axons were not activated by the complete Freund's adjuvant. These studies support the idea that the extracellular signal-related kinases are universal positive axonal signals and that protein kinase G is a limited positive axonal signal. They also establish the association between protein kinase G, the induction of long-term hyperexcitability, and chronic pain in rodents.
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PMID:Activation and retrograde transport of protein kinase G in rat nociceptive neurons after nerve injury and inflammation. 1673 Sep 16

The utility of morphine for the treatment of chronic pain is limited by the development of analgesic tolerance. Adenylyl cyclase (AC) superactivation, induced by chronic opioid agonist administration, is regarded as one of the molecular mechanisms leading to tolerance. In the present work, we tested the role of Raf-1 in morphine-mediated AC superactivation in CHO cells stably expressing the human micro-opioid receptor. We found that pretreatment of CHO cells stably expressing the human micro-opioid receptor with the selective Raf-1 inhibitor, 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one (GW5074, 10 microM, 60 min) completely abolished chronic morphine-mediated AC superactivation (P < 0.01). This finding indicates that Raf-1 may have a crucial role in compensatory feedback regulation of cellular cAMP levels by clinically important opioid analgesics.
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PMID:Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074. 1675 Jan 87

Pathological pain or clinical pain refers to tissue injury-induced inflammatory pain and nerve injury-induced neuropathic pain and is often chronic. Pathological pain is an expression of neural plasticity that occurs both in the peripheral nervous system (e.g., primary sensory nociceptors), termed peripheral sensitization, and in the central nervous system (e.g., dorsal horn and brain neurons), termed central sensitization. Our insufficient understanding of mechanisms underlying the induction and maintenance of injury-induced neuronal plasticity hinders successful treatment for pathological pain. The human genome encodes 518 protein kinases, representing one of the largest protein families. There is growing interest in developing protein kinase inhibitors for the treatment of a number of diseases. Although protein kinases were not favored as targets for analgesics, studies in the last decade have demonstrated important roles of these kinases in regulating neuronal plasticity and pain sensitization. Multiple protein kinases have been implicated in peripheral and central sensitization following intense noxious stimuli and injuries. In particular, mitogen-activated protein kinases (MAPKs), consisting of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), are downstream to many kinases and are activated in primary sensory and dorsal horn neurons by nociceptive activity, growth factors and inflammatory mediators, contributing to the induction and maintenance of pain sensitization via posttranslational, translational, and transcriptional regulation. MAPKs are also activated in spinal glial cells (microglia and astrocytes) after injuries, leading to the synthesis of inflammatory mediators/neuroactive substances that act on nociceptive neurons, enhancing and prolonging pain sensitization. Inhibition of multiple kinases has been shown to attenuate inflammatory and neuropathic pain in different animal models. Development of specific inhibitors for protein kinases to target neurons and glial cells will shed light on the development of new therapies for debilitating chronic pain.
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PMID:Protein kinases as potential targets for the treatment of pathological pain. 1708 30

Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5-/-). We found that AC5-/- mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5-/- mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5-/- mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain.
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PMID:Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5. 1741 Jun 41

Pain symptoms in several chronic pain disorders in women, including irritable bowel syndrome, fluctuate with the menstrual cycle suggesting a gonadal hormone component. In female rats, estrogens modulate visceral sensitivity although the underlying mechanism(s) are unknown. In the present study the effects of 17-beta estradiol on N-methyl-D-aspartate (NMDA) receptor signaling of colorectal nociceptive processing in the spinal cord were examined. Estrogen receptor alpha and the NR1 subunit of the NMDA receptor are co-expressed in dorsal horn neurons, supporting a direct action of estradiol on NMDA receptors. Intrathecal administration of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (APV) dose-dependently attenuated the visceromotor response with greater potency in ovariectomized (OVx) rats compared to OVx with estradiol replacement (E2) rats. Estradiol significantly increased protein expression of NR1 in the lumbosacral spinal cord compared to OVx rats. Colorectal distention significantly increased phosphorylation of NR1ser-897, a PKA phosphorylation site on the NR1 subunit in E2, but not OVx rats. Intrathecal administration of a PKA inhibitor significantly attenuated the visceromotor response, decreased NR1 phosphorylation and increased the potency of APV to attenuate the visceromotor response compared to vehicle-treated E2 rats. These data suggest that estradiol increases spinal processing of visceral nociception by increasing NMDA receptor NR1 subunit expression and increasing site-specific receptor phosphorylation on the NR1 subunit contributing to an increase in NMDA receptor activity.
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PMID:Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat. 1806 1

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major protein kinase that is capable of regulating the activities of many ion channels and receptors. In the present study, the role of CaMKII in the complete Freund's adjuvant (CFA)-induced inflammatory pain was investigated. Intraplantarly injected CFA was found to induce spinal activity of CaMKII (phosphorylated CaMKII), which was blocked by KN93 [[2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine)], a CaMKII inhibitor. Pretreatment with KN93 (i.t.) dose-dependently prevented the development of CFA-induced thermal hyperalgesia and mechanical allodynia. Acute treatment with KN93 (i.t.) also dose-dependently reversed CFA-induced thermal hyperalgesia and mechanical allodynia. The action of KN93 started in 30 min and lasted for at least 2 to 4 h. KN92 (45 nmol i.t.) [2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine], an inactive analog of KN93, showed no effect on CFA-induced CaMKII activation, allodynia, or hyperalgesia. Furthermore, our previous studies identified trifluoperazine, a clinically used antipsychotic drug, to be a potent CaMKII inhibitor. Inhibition of CaMKII activity by trifluoperazine was confirmed in the study. In addition, trifluoperazine (i.p.) dose-dependently reversed CFA-induced mechanical allodynia and thermal hyperalgesia. The drug was also effectively when given orally. In conclusion, our findings support a critical role of CaMKII in inflammatory pain. Blocking CaMKII or CaMKII-mediated signaling may offer a novel therapeutic target for the treatment of chronic pain.
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PMID:Reversal of chronic inflammatory pain by acute inhibition of Ca2+/calmodulin-dependent protein kinase II. 1817 3

Neuropathic pain occurs as a result of peripheral or central nervous system injury. Its pathophysiology involves mainly a central sensitization mechanism that may be correlated to many molecules acting in regions involved in pain processing, such as the spinal cord. It has been demonstrated that reactive oxygen species (ROS) and signaling molecules, such as the serine/threonine protein kinase Akt, are involved in neuropathic pain mechanisms. Thus, the aim of this study was to provide evidence of this relationship. Sciatic nerve transection (SNT) was used to induce neuropathic pain in rats. Western blot analysis of Akt and 4-hydroxy-2-nonenal (HNE)-Michael adducts, and measurement of hydrogen peroxide (H(2)O(2)) in the lumbosacral spinal cord were performed. The main findings were found seven days after SNT, when there was an increase in HNE-Michael adducts formation, total and p-Akt expression, and H(2)O(2) concentration. However, one and 15 days after SNT, H(2)O(2) concentration was raised in both sham (animals that were submitted to surgery without nerve injury) and SNT groups, showing the high sensibility of this ROS to nociceptive afferent stimuli, not only to neuropathic pain. p-Akt also increased in sham and SNT groups one day post injury, but at 3 and 7 days the increase occurred exclusively in SNT animals. Thus, there is crosstalk between intracellular signaling pathways and ROS, and these molecules can act as protective agents in acute pain situations or play a role in the development of chronic pain states.
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PMID:Increase in reactive oxygen species and activation of Akt signaling pathway in neuropathic pain. 1837 70

Migraine headache originates from the stimulation of nerve terminals of trigeminal ganglion neurons that innervate meninges. Characteristic features of migraine pain are not only its delayed onset but also its persistent duration. Current theories propose that endogenous substances released during a migraine attack (the neuropeptide calcitonin gene-related peptide [CGRP] and the neurotrophin nerve growth factor [NGF]) sensitize trigeminal neurons to transmit nociceptive signals to the brainstem, though the mechanisms remain poorly understood. Recent studies indicate that acute, long-lasting sensitization of trigeminal nociceptive neurons occurs via distinct processes involving enhanced expression and function of adenosine triphosphate (ATP)-gated P2X3 receptors known to play a role in chronic pain. In particular, on cultured trigeminal neurons, CGRP (via protein kinase A-dependent signaling) induces a slowly developing upregulation of the ionic currents mediated by P2X3 receptors by enhancing receptor trafficking to the neuronal membrane and activating their gene transcription. Such upregulated receptors acquire the ability to respond repeatedly to extracellular ATP, thus enabling long-lasting signaling of painful stimuli. In contrast, NGF induces rapid, reversible upregulation of P2X3 receptor function via protein kinase C phosphorylation, an effect counteracted by anti-NGF antibodies. The diverse intracellular signaling pathways used by CGRP and NGF show that the sensitization of P2X3 receptor function persists if the action of only one of these migraine mediators is blocked. These findings imply that inhibiting a migraine attack might be most efficient by a combinatorial approach. The different time domains of P2X3 receptor modulation by NGF and CGRP suggest that the therapeutic efficacy of novel antimigraine drugs depends on the time of administration.
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PMID:Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. 1845 72

Glutamate transporters play a crucial role in physiological glutamate homeostasis, neurotoxicity, and glutamatergic regulation of opioid tolerance. However, how the glutamate transporter turnover is regulated remains poorly understood. Here we show that chronic morphine exposure induced posttranscriptional down-regulation of the glutamate transporter EAAC1 in C6 glioma cells with a concurrent decrease in glutamate uptake and increase in proteasome activity, which were blocked by the selective proteasome inhibitor MG-132 or lactacystin but not the lysosomal inhibitor chloroquin. At the cellular level, chronic morphine induced the PTEN (phosphatase and tensin homolog deleted on chromosome Ten)-mediated up-regulation of the ubiquitin E3 ligase Nedd4 via cAMP/protein kinase A signaling, leading to EAAC1 ubiquitination and proteasomal degradation. Either Nedd4 or PTEN knockdown with small interfering RNA prevented the morphine-induced EAAC1 degradation and decreased glutamate uptake. These data indicate that cAMP/protein kinase A signaling serves as an intracellular regulator upstream to the activation of the PTEN/Nedd4-mediated ubiquitin-proteasome system activity that is critical for glutamate transporter turnover. Under an in vivo condition, chronic morphine exposure also induced posttranscriptional down-regulation of the glutamate transporter EAAC1, which was prevented by MG-132, and transcriptional up-regulation of PTEN and Nedd4 within the spinal cord dorsal horn. Thus, inhibition of the ubiquitin-proteasome-mediated glutamate transporter degradation may be an important mechanism for preventing glutamate overexcitation and may offer a new strategy for treating certain neurological disorders and improving opioid therapy in chronic pain management.
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PMID:Morphine induces ubiquitin-proteasome activity and glutamate transporter degradation. 1853 96

The mechanism of embryonic stem (ES) cell therapeutic action remains far from being elucidated. Our recent report has shown that transplantation of ES cells, predifferentiated into neuronal progenitors, prevented appearance of chronic pain behaviors in mice after experimentally induced spinal cord injury. In the current study, we tested the hypothesis that this beneficial effect is mediated by antiapoptotic and regenerative signaling pathways activated in the host tissue by transplanted ES cells. Spinal cord injury was induced by unilateral microinjections of quisqualic acid at spinal levels T12-L2. At 1 week after injury, the pre-differentiated towards neuronal phenotype ES cells were transplanted into the site of injury. Here we show that transplantation of pre-differentiated ES cells activate both brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) signaling pathways in the host tissue, leading to activation of cAMP/PKA, phosporylation of cofilin and synapsin I, and promoting regenerative growth and neuronal survival.
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PMID:Pre-differentiated embryonic stem cells promote neuronal regeneration by cross-coupling of BDNF and IL-6 signaling pathways in the host tissue. 1913 7


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