Nucleotides control the excitability of sensory neurons via two P2Y receptors and a bifurcated signaling cascade

Yousuf, Arsalan; Klinger, Felicia; Schicker, Klaus; Boehm, Stefan

doi:10.1016/j.pain.2011.04.016

Cited by 40 publications

(39 citation statements)

References 48 publications

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“…UTP is an agonist for P2Y 2 and P2Y 4 receptors [29]. P2Y 4 , a Gq-coupled UTP receptor, is expressed in sensory ganglia [33,34], but functional analysis shows low levels of P2Y 4 receptor expression in DRG neurons [8,35]. Suramin has been shown to block all nucleotide-sensitive P2Y receptors with the exception of the P2Y 4 receptor subtype [30].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, P2Y 1 and P2Y 2 receptors have been shown to be the major P2Y subtypes expressed in small-diameter sensory neurons with thin primary afferent fibers including nociceptors [5,6]. In the periphery, activation of P2Y 2 receptors by UTP sensitizes transient receptor potential vanilloid receptor 1 (TRPV1) and contributes to TRPV1-mediated thermal hypersensitivity [7,8]. Activation of P2Y 2 receptors also potentiates mechanosensitive currents in peptidergic nociceptive dorsal root ganglia (DRG) neurons and sensitizes cutaneous C-fiber nociceptors to mechanical stimuli [9].…”

Section: Introductionmentioning

confidence: 99%

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Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

Ren

Gan

et al. 2015

Purinergic Signalling

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Peripheral purinergic signaling plays an important role in nociception. Increasing evidence suggests that metabotropic P2Y receptors are also involved, but little is known about the underlying mechanism. Herein, we report that selective P2Y receptor agonist uridine 5′-triphosphate (UTP) can exert an enhancing effect on the functional activity of acidsensing ion channels (ASICs), key sensors for extracellular protons, in rat dorsal root ganglia (DRG) neurons. First, UTP dose-dependently increased the amplitude of ASIC currents. UTP also shifted the concentration-response curve for proton upwards, with a 56.6±6.4 % increase of the maximal current response to proton. Second, UTP potentiation of proton-gated currents can be mimicked by adenosine 5′-triphosphate (ATP), but not by P2Y1 receptor agonist ADP. Potentiation of UTP was blocked by P2Y receptor antagonist suramin and by inhibition of intracellular G protein, phospholipase C (PLC), protein kinase C (PKC), or protein interacting with C-kinase 1 (PICK1) signaling. Third, UTP altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, UTP dose-dependently exacerbated nociceptive responses to injection of acetic acid in rats. These results suggest that UTP enhanced ASIC-mediated currents and nociceptive responses, which reveal a novel peripheral mechanism underlying UTP-sensitive P2Y 2 receptor involvement in hyperalgesia by sensitizing ASICs in primary sensory neurons.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

Ren

Gan

et al. 2015

Purinergic Signalling

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“…The P2Y 2 receptor-preferring agonist 2-thio-UTP was equipotent to UTP in eliciting these effects, whereas the selective P2Y 1 receptor antagonist MRS2179 largely attenuated the excitatory effects of ADP, but left those of 2-thio-UTP unaltered. Application of either ADP or 2-thio-UTP inhibited K-currents through K V 7 channels, and, in parallel, facilitated cation-current through TRPV 1 channels, suggesting that the excitatory effects of these nucleotides were mediated by either P2Y 1 or P2Y 2 receptor subtypes which acted downstream through a common signaling pathway [51].…”

Section: Modulation Of Pain Transmission By P2y Receptors In Sensory mentioning

confidence: 97%

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

Magni

Ceruti

2013

Biochemical Pharmacology

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Non-standard abbreviations:AR-C126313, 5-(7-chloro-4H-1-thia-3-aza-benzo[f]-4-yl)-3-methyl-6-thioxo-piperadin-2-one; AR-C67085, [[[[(2R,3S,4R,5R)-5-(6-amino-2-propylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]-dichloromethyl]phosphonic acid; AR-C69931MX, [dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl) 3-[7-[[2-(3,4-BDNF, brain-derived neurotrophic factor; BK, bradykinin; CFA, Complete Freund's adjuvant; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglia; FHM1, familial hemiplegic migraine type 1; INS37217, P(1)-(uridine 5')-P(4)-(2'-deoxycytidine 5')tetraphosphate, tetrasodium salt; INS48823, {[(3aR,4R,6R,6aR)-2-benzyl-6-(2,4-dioxo-

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“…In Ca 21 imaging experiments on DRG neurons, we were unable to induce any measurable intracellular Ca 21 release with the P2Y6 selective agonist UDP (data not shown). Expression of P2Y4, a Gq-coupled UTP receptor, has been observed in sensory ganglia (Ruan and Burnstock, 2003), but functional analysis shows low levels of P2Y4 receptor expression in DRG neurons (Sanada et al, 2002;Yousuf et al, 2011). Moreover, mRNA detection studies using reverse transcription polymerase chain reaction or in situ hybridization confirm that P2Y4 is a minor purinoceptor subtype in small-diameter sensory neurons (Sanada et al, 2002) (Kobayashi et al, 2006).…”

Section: P2y2-p2x3 Crosstalk In Drg Neuronsmentioning

confidence: 99%

Control of P2X3 Channel Function by Metabotropic P2Y2 UTP Receptors in Primary Sensory Neurons

Peleshok

Cao

et al. 2012

Mol Pharmacol

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Purinergic signaling contributes significantly to pain mechanisms, and the nociceptor-specific P2X3 ATP receptor channel is considered a target in pain therapeutics. Recent findings suggesting the coexpression of metabotropic P2Y receptors with P2X3 implies that ATP release triggers the activation of both ionotropic and metabotropic purinoceptors, with strong potential for functional interaction. Modulation of native P2X3 function by P2Y receptor activation was investigated in rat dorsal root ganglia (DRG) neurons using whole cell patch-clamp recordings. Application of the selective P2Y receptor agonist UTP decreased peak amplitudes of a,b-meATP-evoked homomeric P2X3-mediated currents, but had no effect on heteromeric P2X2/3-mediated currents. Treatment with phospholipase C inhibitor U73122 significantly reversed P2X3 current inhibition induced by UTP-sensitive P2Y receptor activation. We previously reported the modulation of P2X receptors by phospholipids in DRG neurons and injection of exogenous phosphatidylinositol-4,5-bisphosphate (PIP 2 ) fully reverses UTP-mediated regulation of P2X3 channel activity. Pharmacological as well as functional screening of P2Y receptor subtypes indicates the predominant involvement of P2Y2 receptor in P2X3 inhibition, and immunolocalization confirms a significant cellular coexpression of P2X3 and P2Y2 in rat DRG neurons. In summary, the function of P2X3 ATP receptor can be inhibited by P2Y2-mediated depletion of PIP 2 . We propose that expression of P2Y2 purinoceptor in nociceptive sensory neurons provides an homeostatic mechanism to prevent excessive ATP signaling through P2X3 receptor channels.

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Nucleotides control the excitability of sensory neurons via two P2Y receptors and a bifurcated signaling cascade

Abstract: SummaryAdenosine triphosphate and its degradation product adenosine diphosphate excite sensory neurons via 2 different G protein-coupled receptors, P2Y1 and P2Y2, which mediate inhibition KV7 and sensitization of TRPV1 channels.

Cited by 40 publications

References 48 publications

Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

Control of P2X3 Channel Function by Metabotropic P2Y2 UTP Receptors in Primary Sensory Neurons

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