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

Mo, Gary; Peleshok, Jennifer C.; Cao, Chuanai; Ribeiro‐da‐Silva, Alfredo; Séguéla, Philippe

doi:10.1124/mol.112.082099

Cited by 25 publications

(21 citation statements)

References 45 publications

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“…Lack of the enhancing effect in cells treated with PLC inhibitor U-73122 indicating a PLC-dependent pathway was involved in the ASIC sensitization by activation of UTP-sensitive P2Y receptors. It has been shown that inhibition of P2X3 currents by activation of UTP-sensitive P2Y 2 receptors also requires PLC activation [37]. Further, we found that UTP potentiation of ASIC currents was blocked by intracellular dialysis of PKC inhibitor GF109203X.…”

Section: Discussionsupporting

confidence: 54%

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: Discussionsupporting

confidence: 54%

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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“…It was shown that in rat DRG neurons activation of P2Y2 receptors inhibit P2X3 via PI(4,5)P 2 depletion (Mo et al, 2013). Capsaicin also inhibits P2X3 in TRPV1 expressing cells (Stanchev et al, 2009), and in rat DRG neurons (Piper and Docherty, 2000) but the involvement of phosphoinositides were not examined.…”

Section: Ligand Activated and Chemosensitive Ion Channelsmentioning

confidence: 99%

Phosphoinositide signaling in somatosensory neurons

Rohács

2016

Advances in Biological Regulation

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Somatosensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG) are responsible for detecting thermal and tactile stimuli. They are also the primary neurons mediating pain and itch. A large number of cell surface receptors in these neurons couple to phospholipase C (PLC) enzymes leading to the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and the generation of downstream signaling molecules. These neurons also express many different ion channels, several of which are regulated by phosphoinositides. This review will summarize the knowledge on phosphoinositide signaling in these neurons, with special focus on effects on sensory and other ion channels.

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“…The activation of the purinoceptor P2Y2 by pro-inflammatory nucleotides such as ATP or UTP initiates the PLC pathway through Gq-coupling, activating both SOCE and ROCE by generating IP 3 and DAG, respectively. To examine if TRPC3 contributes to P2Y2-mediated calcium signaling, we applied 100 μM UTP, a selective agonist for P2Y2 receptors [39], on primary DRG cultures for 7 minutes. The addition of Gd 3+ , and hence blockade of Orai function, produced a decrease of calcium influx upon re-addition of calcium to the perfusion solution.…”

Section: Resultsmentioning

confidence: 99%

Contribution of TRPC3 to Store-Operated Calcium Entry and Inflammatory Transductions in Primary Nociceptors

et al. 2014

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BackgroundProlonged intracellular calcium elevation contributes to sensitization of nociceptors and chronic pain in inflammatory conditions. The underlying molecular mechanisms remain unknown but store-operated calcium entry (SOCE) components participate in calcium homeostasis, potentially playing a significant role in chronic pain pathologies. Most G protein-coupled receptors activated by inflammatory mediators trigger calcium-dependent signaling pathways and stimulate SOCE in primary afferents. The aim of the present study was to investigate the role of TRPC3, a calcium-permeable non-selective cation channel coupled to phospholipase C and highly expressed in DRG, as a link between activation of pro-inflammatory metabotropic receptors and SOCE in nociceptive pathways.ResultsUsing in situ hybridization, we determined that TRPC3 and TRPC1 constitute the major TRPC subunits expressed in adult rat DRG. TRPC3 was found localized exclusively in small and medium diameter sensory neurons. Heterologous overexpression of TRPC3 channel subunits in cultured primary DRG neurons evoked a significant increase of Gd3+-sensitive SOCE following thapsigargin-induced calcium store depletion. Conversely, using the same calcium add-back protocol, knockdown of endogenous TRPC3 with shRNA-mediated interference or pharmacological inhibition with the selective TRPC3 antagonist Pyr10 induced a substantial decrease of SOCE, indicating a significant role of TRPC3 in SOCE in DRG nociceptors. Activation of P2Y2 purinoceptors or PAR2 protease receptors triggered a strong increase in intracellular calcium in conditions of TRPC3 overexpression. Additionally, knockdown of native TRPC3 or its selective pharmacological blockade suppressed UTP- or PAR2 agonist-evoked calcium responses as well as sensitization of DRG neurons. These data show a robust link between activation of pro-inflammatory receptors and calcium homeostasis through TRPC3-containing channels operating both in receptor- and store-operated mode.ConclusionsOur findings highlight a major contribution of TRPC3 to neuronal calcium homeostasis in somatosensory pathways based on the unique ability of these cation channels to engage in both SOCE and receptor-operated calcium influx. This is the first evidence for TRPC3 as a SOCE component in DRG neurons. The flexible role of TRPC3 in calcium signaling as well as its functional coupling to pro-inflammatory metabotropic receptors involved in peripheral sensitization makes it a potential target for therapeutic strategies in chronic pain conditions.

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

Cited by 25 publications

References 45 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

Phosphoinositide signaling in somatosensory neurons

Contribution of TRPC3 to Store-Operated Calcium Entry and Inflammatory Transductions in Primary Nociceptors

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