Modulation of Transient Receptor Potential Vanilloid 4-Mediated Membrane Currents and Synaptic Transmission by Protein Kinase C

Cao, Deshou; Yu, Shuang-Quan; Premkumar, Louis S.

doi:10.1186/1744-8069-5-5

Cited by 88 publications

(88 citation statements)

References 54 publications

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“…DRG neurons express other ion channels involved in nociceptor sensitization to mechanical stimuli that are possible PKC substrates. These include Na V 1.3 (48), TRPV4 (37,(49)(50)(51), and acid-sensing ion channels (52,53). TRPV4 in particular is a candidate, since the selective PKCε inhibitor, εV1-2, blocks TRPV4-dependent mechanical hyperalgesia (37).…”

Section: Discussionmentioning

confidence: 99%

PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice

Chandra

McMahon

et al. 2012

J. Clin. Invest.

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Mechanical hyperalgesia is a common and potentially disabling complication of many inflammatory and neuropathic conditions. Activation of the enzyme PKCε in primary afferent nociceptors is a major mechanism that underlies mechanical hyperalgesia, but the PKCε substrates involved downstream are not known. Here, we report that in a proteomic screen we identified the Na V 1.8 sodium channel, which is selectively expressed in nociceptors, as a PKCε substrate. PKCε-mediated phosphorylation increased Na V 1.8 currents, lowered the threshold voltage for activation, and produced a depolarizing shift in inactivation in wild-type -but not in PKCε-null -sensory neurons. PKCε phosphorylated Na V 1.8 at S1452, and alanine substitution at this site blocked PKCε modulation of channel properties. Moreover, a specific PKCε activator peptide, ψεRACK, produced mechanical hyperalgesia in wild-type mice but not in Scn10a -/-mice, which lack Na V 1.8 channels. These studies demonstrate that Na V 1.8 is an important, direct substrate of PKCε that mediates PKCε-dependent mechanical hyperalgesia. IntroductionTissue damage, inflammation, and neuropathic disorders often produce hyperalgesia, a state of increased sensitivity to painful stimuli. Sensitization of primary afferent nociceptors by inflammatory mediators or by nerve damage produces hyperalgesia, a major clinical problem. One well-established, important regulator of both inflammatory and neuropathic nociceptor sensitization is the ε isoform of PKC (PKCε). PKCε is activated by bradykinin and contributes to bradykinin-mediated sensitization of nociceptors to heat (1). PKCε also mediates mechanical hyperalgesia induced by epinephrine, NGF, or carrageenan and visceral inflammatory pain evoked by intraperitoneal administration of acetic acid (2). In addition, PKCε is a critical mediator of mechanical hyperalgesia in a priming model of chronic pain induced by carrageenan or a selective peptide activator of PKCε, ψεRACK (3), and of mechanical hyperalgesia in rodent models of alcoholic (4), diabetic (5), and vincristine neuropathy (6). The polymodal receptor channel transient receptor potential vanilloid 1 (TRPV1) is a PKCε substrate that contributes to thermal hyperalgesia (7,8), but the peripheral substrates involved in PKCε-induced mechanical hyperalgesia are not known. Identifying these substrates is of clinical interest since mechanical hyperalgesia is very common and can be a disabling feature, particularly in neuropathic pain syndromes.In this study, we used a chemical genetics approach (9) to specifically detect direct protein substrates of PKCε in dorsal root ganglion (DRG) cells and found that the tetrodotoxin-resistant (TTX-R) sodium channel Na V 1.8 is a PKCε substrate. Na V 1.8 channels are selectively expressed in peripheral sensory neurons of neonatal and adult DRG and trigeminal ganglia (10-12). Studies with Scn10a -/-mice, Na V 1.8 inhibitors, antisense oligonucleotides, and

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Section: Discussionmentioning

confidence: 99%

PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice

Chandra

McMahon

et al. 2012

J. Clin. Invest.

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“…Coexpression of the two receptors was observed in 20% of rat urothelial cells (167). TRPV4 may also be expressed in bladder afferents; ϳ30% of L6 dorsal root ganglia neurons that project to the urinary bladder coexpressed TRPV1 and TRPV4 (57,66).…”

Section: Trp Channel Antagonistsmentioning

confidence: 99%

Urothelial Signaling

Birder

Andersson

2013

Physiological Reviews

400

362

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The urothelium, which lines the inner surface of the renal pelvis, the ureters, and the urinary bladder, not only forms a high-resistance barrier to ion, solute and water flux, and pathogens, but also functions as an integral part of a sensory web which receives, amplifies, and transmits information about its external milieu. Urothelial cells have the ability to sense changes in their extracellular environment, and respond to chemical, mechanical and thermal stimuli by releasing various factors such as ATP, nitric oxide, and acetylcholine. They express a variety of receptors and ion channels, including P2X3 purinergic receptors, nicotinic and muscarinic receptors, and TRP channels, which all have been implicated in urothelial-neuronal interactions, and involved in signals that via components in the underlying lamina propria, such as interstitial cells, can be amplified and conveyed to nerves, detrusor muscle cells, and ultimately the central nervous system. The specialized anatomy of the urothelium and underlying structures, and the possible communication mechanisms from urothelial cells to various cell types within the bladder wall are described. Changes in the urothelium/ lamina propria ("mucosa") produced by different bladder disorders are discussed, as well as the mucosa as a target for therapeutic interventions.

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“…This value was linearly correlated (r 2 = 0.97) to the amount of charge movement diameter, and blood pressure. Furthermore, binding of AngII to its receptor activates a signaling cascade that culminates in the activation of PKC in arterial myocytes, and activation of this kinase seems to increase the activity of TRPV4 channels in neurons (Cao et al, 2009). At present, however, whether activation of AngII-PKC signaling modulates TRPV4 channel function in arterial myocytes is unknown.…”

Section: Chemicals and Statisticsmentioning

confidence: 99%

Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle

Mercado¹,

Baylie²,

Navedo³

et al. 2014

J Cell Biol

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Modulation of Transient Receptor Potential Vanilloid 4-Mediated Membrane Currents and Synaptic Transmission by Protein Kinase C

Cited by 88 publications

References 54 publications

PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice

PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice

Urothelial Signaling

Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle

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