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)

Capsaicin-activated channels present in sensory neurons are ligand-gated cation channels that largely account for mediating some types of pain. The cAMP-dependent protein kinase (PKA) signal pathway was suggested to mediate the prostaglandin-induced enhancement of capsaicin-evoked inward current (I(CAP)) in rat sensory neurons. It is not clear, however, whether PKA acts directly on the capsaicin-sensitive channel that is responsible for I(CAP). To address this issue, we overexpressed the cloned capsaicin receptor, VR1, in heterologous expression systems such as Xenopus oocytes or Aplysia R2 neuron and stimulated PKA pathways. As a result, activation of PKA by applying either 8-bromo-cAMP or forskolin with 3-isobutyl-1-methylxanthine or through activation of beta(2) adrenergic receptors failed to enhance I(CAP) in oocytes or R2 neurons expressing VR1. Our results raise two possibilities. (1) Direct phosphorylation of VR1 by PKA may not be responsible for the sensitization; instead, phosphorylation of regulatory proteins associated with VR1 would account for the sensitization of I(CAP) evoked by prostaglandin E(2) in dorsal root ganglion (DRG) neurons. (2) DRG neurons may have a different PKA signaling mechanism that is not replicable in Xenopus oocytes or Aplysia R2 neurons.
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PMID:The cAMP-dependent kinase pathway does not sensitize the cloned vanilloid receptor type 1 expressed in xenopus oocytes or Aplysia neurons. 1086 15

The transient receptor potential (TRP) protein superfamily consists of a diverse group of Ca(2+) permeable nonselective cation channels that bear structural similarities to Drosophila TRP. TRP-related proteins play important roles in nonexcitable cells, as demonstrated by the recent finding that a mammalian TRPC protein is expressed in endothelial cells and functions in vasorelaxation. However, an emerging theme is that many TRP-related proteins are expressed predominantly in the nervous system and function in sensory physiology. The TRP superfamily can be divided into six subfamilies, the first of which is composed of the "classical TRPs" (TRPC subfamily). These proteins all share the common features of three to four ankryin repeats, >/=30% amino acid homology over >/=750 amino acids, and a gating mechanism that operates through phospholipase C. Some classical TRPs may be store-operated channels (SOCs), which are activated by release of Ca(2+) from internal stores. The mammalian TRPC proteins are also expressed in the central nervous system, and several are highly enriched in the brain. One TRPC protein has been implicated in the pheromone response. The archetypal TRP, Drosophila TRP, is predominantly expressed in the visual system and is required for phototransduction. Many members of a second subfamily (TRPV) function in sensory physiology. These include VR1 and OSM-9, which respond to heat, osmolarity, odorants, and mechanical stimuli. A third subfamily, TRPN, includes proteins with many ankyrin repeats, one of which, NOMPC, participates in mechanotransduction. Among the members of a fourth subfamily, TRPM, is a putative tumor suppressor termed melastatin, and a bifunctional protein, TRP-PLIK, consisting of a TRPM channel fused to a protein kinase. PKD2 and mucolipidin are the founding members of the TRPP and TRPML subfamilies, respectively. Mutations in PKD2 are responsible for polycystic kidney disease, and mutations in mucolipidin result in a severe neurodegenerative disorder. Recent studies suggest that alterations in the activities of SOC and TRP channels may be at the heart of several additional neurodegenerative diseases. Thus, TRP channels may prove to be important new targets for drug discovery.
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PMID:Physiology, phylogeny, and functions of the TRP superfamily of cation channels. 1175 62

Inflammatory mediators not only activate "pain-"sensing neurons, the nociceptors, to trigger acute pain sensations, more important, they increase nociceptor responsiveness to produce inflammatory hyperalgesia. For example, prostaglandins activate G(s)-protein-coupled receptors and initiate cAMP- and protein kinase A (PKA)-mediated processes. We demonstrate for the first time at the cellular level that heat-activated ionic currents were potentiated after exposure to the cAMP activator forskolin in rat nociceptive neurons. The potentiation was prevented in the presence of the selective PKA inhibitor PKI(14-22), suggesting PKA-mediated phosphorylation of the heat transducer protein. PKA regulatory subunits were found in close vicinity to the plasma membrane in these neurons, and PKA catalytic subunits only translocated to the cell periphery when activated. The translocation and the current potentiation were abolished in the presence of an A-kinase anchoring protein (AKAP) inhibitor. Similar current changes after PKA activation were obtained from human embryonic kidney 293t cells transfected with the wild-type heat transducer protein vanilloid receptor 1 (VR-1). The forskolin-induced current potentiation was greatly reduced in cells transfected with VR-1 mutants carrying point mutations at the predicted PKA phosphorylation sites. The heat transducer VR-1 is therefore suggested as the molecular target of PKA phosphorylation, and potentiation of current responses to heat depends on phosphorylation at predicted PKA consensus sites. Thus, the PKA/AKAP/VR-1 module presents as the molecular correlate of G(s)-mediated inflammatory hyperalgesia.
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PMID:PKA/AKAP/VR-1 module: A common link of Gs-mediated signaling to thermal hyperalgesia. 1204 81

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

When capsaicin, the pungent compound in hot pepper, is applied to epithelia it produces pain, allodynia, and hyperalgesia. We investigated, using whole cell path clamp, whether some of these responses induced by capsaicin could be a consequence of capsaicin blocking I(A) currents, a reduction in which, such as occurs in injury, increases neuronal excitability. In capsaicin-sensitive (CS) rat trigeminal ganglion (TG) neurons, capsaicin inhibited I(A) currents in a dose-dependent manner. I(A) currents were reduced 49% by 1 microM capsaicin. In capsaicin-insensitive (CIS) rat TG neurons, or small-diameter mouse VR1-/- neurons, 1 microM capsaicin inhibited I(A) currents 9 and 3%, respectively. These data suggest that in CS neurons the vast majority of the capsaicin-induced inhibition of I(A) currents occurs as a consequence of the activation of vanilloid receptors. Capsaicin (1 microM) did not alter the I(A) conductance-voltage relationship but shifted the inactivation-voltage curve about 15 mV to hyperpolarizing voltages, thereby increasing the number of inactivated I(A) channels at the resting potential. I(A) currents were relatively unaffected by 1 mM CTP-cAMP or 500 nM phorbol-12, 13-dibuterate (a protein kinase C agonist) but were inhibited by 20-30% with either 1 mM CTP-cGMP or 25 microM N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide HCl (a calcium-calmodulin kinase inhibitor). In the presence of 0.5 microM KT5823, an inhibitor of protein kinase G (PKG) pathways, 1 microM capsaicin inhibited I(A) by only 26%. In summary, in CS neurons, capsaicin decreases I(A) currents through the activation of vanilloid receptors. That activation, partially through the activation of cGMP-PKG and calmodulin-dependent pathways should result in increased excitability of capsaicin-sensitive nociceptors.
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PMID:Modulation of IA currents by capsaicin in rat trigeminal ganglion neurons. 1262 18

Nerve growth factor (NGF) causes a rapid sensitisation of nociceptive sensory neurones to painful thermal stimuli owing to an action on the heat and capsaicin receptor TRPV1 (formerly known as VR1). We have developed a new technique to study this rapid sensitisation of TRPV1 by monitoring the effects of NGF on the increase in intracellular calcium concentration ([Ca2+]i) following exposure to capsaicin. Brief applications of capsaicin caused a rise in [Ca2+]i, and NGF was found to enhance this rise in 37 % of capsaicin-responsive neurones within 2 min. Pathways responsible for transducing the sensitisation of TRPV1 by TrkA, the NGF receptor, were characterised by observing the effects of inhibitors of key members of NGF-activated second messenger signalling cascades. Specific inhibitors of the ras/MEK (mitogen-activated protein and extracellular signal-regulated kinases) pathway and of phospholipase C did not abolish the NGF-induced sensitisation, but wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), totally abolished the effect of NGF. Pharmacological blockade of protein kinase C (PKC) or calcium-calmodulin-dependent protein kinase II (CaMK II) activation also prevented NGF-induced sensitisation, while blockade of protein kinase A (PKA) was without effect. These data indicate that the crucial early pathway activated by NGF involves PI3K, while PKC and CaMK II are also involved, probably at subsequent stages of the NGF-activated signalling pathway.
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PMID:Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. 1281 88

The effect of anandamide, which activates both the cannabinoid 1 (CB1) receptor and the vanilloid receptor 1 (VR1), was studied on calcitonin gene-related peptide (CGRP) release from cultured primary sensory neurons, the majority of which coexpress the CB1 receptor and VR1. Concentrations of anandamide < 1 micro m produced a small but significant CB1 receptor-mediated inhibition of basal CGRP release while higher concentrations induced VR1-mediated CGRP release. The excitatory effect of anandamide was potentiated by the CB1 receptor antagonist SR141716A. In the presence of SR141716A at concentrations < 100 nm, anandamide was equipotent with capsaicin in stimulating CGRP release. However, at higher concentrations anandamide produced more CGRP release than equimolar concentrations of capsaicin. Three and ten nanomolar anandamide inhibited the capsaicin-evoked CGRP release. In the presence of SR141716A, treatments which activated protein kinase A, protein kinase C and phospholipase C significantly potentiated the anandamide-evoked CGRP release at all anandamide concentrations. Although this potentiation was reduced when the CB1 receptor antagonist was omitted from the buffer, the CGRP release evoked by 300 nm and 1 micro m anandamide was still significantly larger than that seen with nonpotentiated cells. These data indicate that anandamide may regulate CGRP release from capsaicin-sensitive primary sensory neurons in vivo, and that the net effect of anandamide on transmitter release from capsaicin-sensitive primary sensory neurons depends on the concentration of anandamide and the state of the CB1 receptor and VR1. These findings also suggest that anandamide could be one of the molecules responsible for the development of inflammatory heat hyperalgesia.
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PMID:Anandamide regulates neuropeptide release from capsaicin-sensitive primary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro. 1282 68

Proinflammatory prostaglandin E2 is known to sensitize sensory neurons to noxious stimuli. This sensitization is mediated by the cAMP-dependent protein kinase (PKA) signal pathway. The capsaicin receptor TRPV1, a non-selective cation channel of sensory neurons involved in the sensation of inflammatory pain, is a target of PKA-mediated phosphorylation. Our goal was to investigate the influence of PKA on Ca(2+)-dependent desensitization of capsaicin-activated currents. By using site-directed mutagenesis, we created point mutations at PKA consensus sites and studied wild-type and mutant channels transiently expressed in HEK293t cells under whole-cell voltage clamp. We found that forskolin, a stimulator of adenylate cyclase, decreased desensitization of TRPV1. The selective PKA inhibitor H89 inhibited this effect. Mimicking phosphorylation at PKA consensus sites by replacing Ser-6, Ser-116, Thr-144, Thr-370, Ser-502, Ser-774, or Ser-820 with aspartate resulted in five mutations (S116D, T144D, T370D, S774D, and S820D) that exhibited decreased desensitization as well. However, disrupting phosphorylation by replacing respective sites with alanine resulted in four mutations (S6A, T144A, T370A, and S820A) with desensitization properties resembling those of the aspartate mutations. Significant changes in relative permeabilities for Ca2+ over Na+ or in capsaicin sensitivity could not explain changes in desensitization properties of mutant channels. In mutations S116A, S116D, T370A, and T370D, pretreatment of cells with forskolin did not reduce desensitization as compared with wild-type and other mutant channels. We conclude that Ser-116 and possibly Thr-370 are the most important residues involved in the mechanism of PKA-dependent reduction of desensitization of capsaicin-activated currents.
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PMID:Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway. 1450 58

Vanilloid receptor 1 (VR1), a capsaicin receptor, is known to play a major role in mediating inflammatory thermal nociception. Although the physiological role and biophysical properties of VR1 are known, the mechanism of its activation by ligands is poorly understood. Here we show that VR1 must be phosphorylated by Ca2+-calmodulin dependent kinase II (CaMKII) before its activation by capsaicin. In contrast, the dephosphorylation of VR1 by calcineurin leads to a desensitization of the receptor. Moreover, point mutations in VR1 at two putative consensus sites for CaMKII failed to elicit capsaicin-sensitive currents and caused a concomitant reduction in VR1 phosphorylation in vivo. Such mutants also lost their high affinity binding with [3H]resiniferatoxin, a potent capsaicin receptor agonist. We conclude that the dynamic balance between the phosphorylation and dephosphorylation of the VR1 channel by CaMKII and calcineurin, respectively, controls the activation/desensitization states by regulating VR1 binding. Furthermore, because sensitization by protein kinase A and C converge at these sites, phosphorylation stress in the cell appears to control a wide range of excitabilities in response to various adverse stimuli.
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PMID:Phosphorylation of vanilloid receptor 1 by Ca2+/calmodulin-dependent kinase II regulates its vanilloid binding. 1463 Sep 12

Cannabinoids include not only plant-derived compounds (of which delta9-tetrahydrocannabinol is the primary psychoactive ingredient of cannabis), but also synthetic agents and endogenous substances termed endocannabinoids which include anandamide (2-arachidonoylethanolamide) and 2-arachidonoylglycerol. Cannabinoids act on specific, G-protein-coupled, receptors which are currently divided into two types, CB1 and CB2. Relatively selective agonists and antagonists for these receptors have been developed, although one agent (SR141716A) widely used as an antagonist at CB1 receptors has non-cannabinoid receptor-mediated effects at concentrations which are often used to define the presence of the CB1 receptor. Both cannabinoid receptors are primarily coupled to Gi/o proteins and act to inhibit adenylyl cyclase. Stimulation of CB1 receptors also modulates the activity of K+ and Ca2+ channels and of protein kinase pathways including protein kinase B (Akt) which might mediate effects on apoptosis. CB, receptors may activate the extracellular signal-regulated kinase cascade through ceramide signalling. Cannabinoid actions on the cardiovascular system have been widely interpreted as being mediated by CB1 receptors although there are a growing number of observations, particularly in isolated heart and blood vessel preparations, that suggest that other cannabinoid receptors may exist. Interestingly, the currently identified cannabinoid receptors appear to be related to a wider family of lipid receptor, those for the lysophospholipids, which are also linked to Gi/o protein signalling. Anandamide also activates vanilloid VR1 receptors on sensory nerves and releases the vasoactive peptide, calcitonin gene-related peptide (CGRP), which brings about vasodilatation through its action on CGRP receptors. Current evidence suggests that endocannabinoids have important protective roles in pathophysiological conditions such as shock and myocardial infarction. Therefore, their cardiovascular effects and the receptors mediating them are the subject of increasing investigative interest.
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PMID:Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling. 1500 77


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