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)

Mechanosensitive (MS) ion channels are present in a variety of cells. However, very little is known about the ion channels that account for mechanical sensitivity in sensory neurons. We identified the two most frequently encountered but distinct types of MS channels in 1390 of 2962 membrane patches tested in cultured dorsal root ganglion neurons. The two MS channels exhibited different thresholds, thus named as low-threshold (LT) and high-threshold (HT) MS channels, and sensitivity to pressure. The two channels retained different single-channel conductances and current-voltage relationships: LT and HT channels elicited large- and small-channel conductance with outwardly rectifying and linear I-V relationships, respectively. Both LT and HT MS channels were permeable to monovalent cations and Ca2+ and were blocked by gadolinium, a blocker of MS channels. Colchicine and cytochalasin D markedly reduced the activities of the two MS channels, indicating that cytoskeletal elements support the mechanosensitivity. Both types of MS channels were found primarily in small sensory neurons with diameters of <30 microm. Furthermore, HT MS channels were sensitized by a well known inducer of mechanical hyperalgesia, prostaglandin E2, via the protein kinase A pathway. We identified two distinct types of MS channels in sensory neurons that probably give rise to the observed MS whole-cell currents and transduce mechanical stimuli to neural signals involved in somatosensation, including pain.
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PMID:Mechanosensitive ion channels in cultured sensory neurons of neonatal rats. 1185 Apr 51

Mechanisms underlying neuropathic pain states are poorly understood. We have compared mechanisms mediating enhanced nociception of four established models of neuropathic pain produced by very different types of insults to the peripheral nervous system: streptozotocin-induced hyperalgesia, a model of diabetic (metabolic) peripheral neuropathy, vincristine-induced hyperalgesia, a model of chemotherapeutic agent (toxic) peripheral neuropathy, and chronic constriction injury and partial nerve ligation, models of trauma-induced painful neuropathies. All four models resulted in prolonged mechanical hyperalgesia (>30% decrease in mechanical nociceptive threshold) and allodynia (detected by 10-209-mN-intensity von Frey hairs). In vincristine- and streptozotocin-induced hyperalgesia, the protein kinase A, protein kinase C and nitric oxide second messenger pathways in the periphery contributed to the hyperalgesia, while N-methyl-D-aspartate (NMDA) receptor-mediated events were not detected. None of these second messengers nor the NMDA receptor, which can contribute to peripheral sensitization of nociceptors, contributed to chronic constriction injury- and partial nerve ligation-induced hyperalgesia. In all four models the hyperalgesia was not antagonized by peripheral administration of a mu-opioid agonist.Our findings support the presence of a common abnormality in second messenger signaling in the periphery to the maintenance of two very different models of non-traumatic neuropathic pain, not shared by models of trauma-induced neuropathic pain.
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PMID:Different peripheral mechanisms mediate enhanced nociception in metabolic/toxic and traumatic painful peripheral neuropathies in the rat. 1198 24

Injection of capsaicin into the skin results in pain, primary heat and mechanical hyperalgesia, and secondary mechanical allodynia and hyperalgesia. Sensory receptors in the area of secondary mechanical allodynia and hyperalgesia are unaffected, and so the sensory changes must be due to central actions of the initial intense nociceptive discharge that follows the capsaicin injection. Central sensitization of the responses of spinothalamic tract neurons lasts several hours, but can be prevented by spinal cord administration of non-NMDA and NMDA glutamate receptor antagonists or NK1 substance P receptor antagonists. The long-lasting increase in excitability of spinothalamic tract cells depends on the activation of several second messenger cascades (PKC, PKA, and NO/PKG signal transduction pathways). The excitability change also depends on activation of calcium/calmodulin-dependent kinase II, which is consistent with the proposal that this central sensitization response is a form of long-term potentiation.
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PMID:Role of neurotransmitters in sensitization of pain responses. 1200 17

The ability to remember potential dangers in an environment is necessary to the survival of animals and humans. The cyclic AMP responsive element binding protein (CREB) is a key transcription factor in synaptic plasticity and memory consolidation. We have found that in CaMKIV(-/-) mice--which are deficient in a component of the calcium calmodulin-dependent protein kinase (CaMK) pathway, a major pathway of CREB activation--fear memory, but not persistent pain, was significantly reduced. CREB activation by fear conditioning and synaptic potentiation in the amygdala and cortical areas was reduced or blocked. We propose that cognitive memory related to a noxious shock can be disassociated from behavioral responses to tissue injury and inflammation.
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PMID:Calcium calmodulin-dependent protein kinase IV is required for fear memory. 1200 82

Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and is characterized by severe pain, increased frequency of micturition, and chronic inflammation. Characterizing the molecular fingerprint (gene profile) of IC will help elucidate the mechanisms involved and suggest further approaches for therapeutic intervention. Therefore, in the present study we used established animal models of cystitis to determine the time course of bladder inflammatory responses to antigen, Escherichia coli lipopolysaccharide (LPS), and substance P (SP) by morphological analysis and cDNA microarrays. The specific aim of the present study was to compare bladder inflammatory responses to antigen, LPS, and SP by morphological analysis and cDNA microarray profiling to determine whether bladder responses to inflammation elicit a specific universal gene expression response regardless of the stimulating agent. During acute bladder inflammation, there was a predominant infiltrate of polymorphonuclear neutrophils into the bladder. Time-course studies identified early, intermediate, and late genes that were commonly up-regulated by all three stimuli. These genes included: phosphodiesterase 1C, cAMP-dependent protein kinase, iNOS, beta-NGF, proenkephalin B and orphanin, corticotrophin-releasing factor (CRF) R, estrogen R, PAI2, and protease inhibitor 17, NFkB p105, c-fos, fos-B, basic transcription factors, and cytoskeleton and motility proteins. Another cluster indicated genes that were commonly down-regulated by all three stimuli and included HSF2, NF-kappa B p65, ICE, IGF-II and FGF-7, MMP2, MMP14, and presenilin 2. Furthermore, we determined gene profiles that identify the transition between acute and chronic inflammation. During chronic inflammation, the urinary bladder presented a predominance of monocyte/macrophage infiltrate and a concomitant increase in the expression of the following genes: 5-HT 1c, 5-HTR7, beta 2 adrenergic receptor, c-Fgr, collagen 10 alpha 1, mast cell factor, melanocyte-specific gene 2, neural cell adhesion molecule 2, potassium inwardly-rectifying channel, prostaglandin F receptor, and RXR-beta cis-11-retinoic acid receptor. We conclude that microarray analysis of genes expressed in the bladder during experimental inflammation may be predictive of outcome. Further characterization of the inflammation-induced gene expression profiles obtained here may identify novel biomarkers and shed light into the etiology of cystitis.
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PMID:Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. 1205 14

Pain and hyperalgesia from deep somatic tissue (i.e., muscle and joint) are processed differently from that from skin. This study examined differences between deep and cutaneous tissue allodynia and the role of cAMP in associated behavioral changes. Capsaicin was injected into the plantar aspect of the skin, plantar muscles of the paw, or ankle joint, and responses to mechanical and heat stimuli were assessed until allodynia resolved. Capsaicin injected into skin resulted in a secondary mechanical allodynia and heat hypoalgesia lasting approximately 3 hr. In contrast, capsaicin injection into muscle or joint resulted in a long-lasting bilateral (1-4 weeks) mechanical allodynia with a simultaneous unilateral heat hypoalgesia. The pattern and degree of inflammation were similar when capsaicin was injected into skin, muscle, or joint, with peak increases 24 hr after injection. Heat hypoalgesia that occurs after injection into deep tissue was reversed by spinal blockade of adenylate cyclase or protein kinase A (PKA). Interestingly, mechanical allodynia was reversed if adenylate cyclase or PKA inhibitors were administered spinally 24 hr, but not 1 week, after injection of capsaicin. Spinally administered 8-bromo-cAMP resulted in a similar pattern, with heat hypoalgesia and mechanical allodynia occurring simultaneously. Thus, injection of capsaicin into deep tissues results in a longer-lasting mechanical allodynia and heat hypoalgesia compared with injection of capsaicin into skin. The mechanical allodynia depends on early activation of the cAMP pathway during the first 24 hr but is independent of the cAMP pathway by 1 week after injection of capsaicin.
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PMID:Stimulation of deep somatic tissue with capsaicin produces long-lasting mechanical allodynia and heat hypoalgesia that depends on early activation of the cAMP pathway. 1209 20

The capsaicin receptor, VR1 (also known as TRPV1), is a ligand-gated ion channel expressed on nociceptive sensory neurons that responds to noxious thermal and chemical stimuli. Capsaicin responses in sensory neurons exhibit robust potentiation by cAMP-dependent protein kinase (PKA). In this study, we demonstrate that PKA reduces VR1 desensitization and directly phosphorylates VR1. In vitro phosphorylation, phosphopeptide mapping, and protein sequencing of VR1 cytoplasmic domains delineate several candidate PKA phosphorylation sites. Electrophysiological analysis of phosphorylation site mutants clearly pinpoints Ser116 as the residue responsible for PKA-dependent modulation of VR1. Given the significant roles of VR1 and PKA in inflammatory pain hypersensitivity, VR1 phosphorylation at Ser116 by PKA may represent an important molecular mechanism involved in the regulation of VR1 function after tissue injury.
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PMID:cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. 1219 71

Local perfusion of the dorsal root ganglion (DRG) with tumor necrosis factor alpha (TNF-alpha) in rats induces cutaneous hypersensitivity to mechanical stimuli. Thus we investigated the cellular mechanisms of TNF-alpha-induced mechanical hyperalgesia. The L(4) and L(5) DRGs with the sciatic nerves attached were excised from rats for in vitro dorsal root microfilament recording. After baseline recording for 15 min, TNF-alpha (0.001, 0.01, 0.1, or 1 ng/ml) was applied to the DRG for 15 min, followed by washout for at least 30 min. Alternatively, H-89 or Rp-cAMPS, two specific cAMP-dependent protein kinase (PKA) inhibitors, was added to the perfusion solution for 15 min prior to TNF-alpha application. TNF-alpha (1 ng/ml) induced neuronal discharges in 67% (14/21) of C fibers and 27% (4/15) of Abeta fibers when applied topically to the DRG. Acute TNF-alpha application not only evoked discharges in silent fibers, but also enhanced ongoing activity of spontaneously active fibers and increased neuronal sensitivity to electrical stimulation of the peripheral nerves. H-89 (10 microM) and Rp-cAMPS (100 microM) each completely blocked the TNF-alpha-evoked response in most C and Abeta fibers tested but did not affect fiber conductivity. Our results demonstrates that exogenous inflammatory cytokines such as TNF-alpha can elicit a PKA-dependent response in sensory neurons and thus strongly suggest that endogenous TNF-alpha may contribute to the development of certain pathological pain states.
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PMID:Acute topical application of tumor necrosis factor alpha evokes protein kinase A-dependent responses in rat sensory neurons. 1220 59

Substance P is a member of the tachykinin family of neuropeptides that plays an important role in pain transmission, neurogenic inflammatory diseases and the adaptive response to stress. Substance P exerts its biological activities via binding to a G-protein coupled receptor of the neurokinin (NK) receptor family. Here, we show by Western blot experiments that substance P induced a transient synthesis of the zinc finger transcriptional regulator Egr-1 in human glioma cells. Substance P-induced stimulation of Egr-1 biosynthesis was completely inhibited by the mitogen-activated protein kinase kinase inhibitor PD98059 and by AG1487, an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor. These results indicate that transactivation of the EGF receptor as well as stimulation of the mitogen activated/extracellular signal-regulated protein kinase (ERK) are essential for substance P/NK-1 receptor-induced activation of Egr-1 biosynthesis. Moreover, we show that the signaling cascade initiated by substance P or EGF are indistinguishable, including the activation of the EGF receptor, the activation of ERK, and the final stimulation of Egr-1 biosynthesis. The synthesis of Egr-1 in glioma cells as a result of substance P stimulation suggests that substance P exerts long-term effects in glioma cells via Egr-1-mediated gene transcription.
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PMID:Substance P induced biosynthesis of the zinc finger transcription factor Egr-1 in human glioma cells requires activation of the epidermal growth factor receptor and of extracellular signal-regulated protein kinase. 1238 23

Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular protons. They are expressed in central and sensory neurons where they are involved in neuromodulation and in pain perception. Recently, the PDZ domain-containing protein PICK1 (protein interacting with C-kinase) has been shown to interact with ASIC1a and ASIC2a, raising the possibility that protein kinase C (PKC) could regulate ASICs. We now show that the amplitude of the ASIC2a current, which was only modestly increased ( approximately +30%) by the PKC activator 1-oleyl-2-acetyl-sn-glycerol (OAG, 50 microm) in the absence of PICK1, was strongly potentiated ( approximately +300%) in the presence of PICK1. This PICK1-dependent regulatory effect was inhibited in the presence of a PKC inhibitory peptide and required the PDZ domain of PICK1 as well as the PDZ-binding domain of ASIC2a. We have also shown the direct PICK1-dependent phosphorylation of ASIC2a by [(32)P]phosphate labeling and immunoprecipitation and identified a major phosphorylation site, (39)TIR, on the N terminus part of ASIC2a. The OAG-induced increase in ASIC2a current amplitude did not involve any change in the unitary conductance of the ASIC2a channel, whether co-expressed with PICK1 or not. These data provide the first demonstration of a regulation of ASICs by protein kinase phosphorylation and its potentiation by the partner protein PICK1.
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PMID:Protein kinase C stimulates the acid-sensing ion channel ASIC2a via the PDZ domain-containing protein PICK1. 1239 60


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