Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors
- PMID: 24965271
- PMCID: PMC4118315
- DOI: 10.1186/1744-8069-10-43
Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors
Abstract
Background: Prolonged 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.
Results: Using 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.
Conclusions: Our 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.
Figures






Similar articles
-
Transient receptor potential canonical 3 (TRPC3) is required for IgG immune complex-induced excitation of the rat dorsal root ganglion neurons.J Neurosci. 2012 Jul 11;32(28):9554-62. doi: 10.1523/JNEUROSCI.6355-11.2012. J Neurosci. 2012. PMID: 22787041 Free PMC article.
-
A TRPC1/TRPC3-mediated increase in store-operated calcium entry is required for differentiation of H19-7 hippocampal neuronal cells.J Biol Chem. 2004 Oct 15;279(42):43392-402. doi: 10.1074/jbc.M408959200. Epub 2004 Aug 5. J Biol Chem. 2004. PMID: 15297455
-
Store-operated Ca2+ channels formed by TRPC1, TRPC6 and Orai1 and non-store-operated channels formed by TRPC3 are involved in the regulation of NADPH oxidase in HL-60 granulocytes.Cell Calcium. 2008 Nov;44(5):492-506. doi: 10.1016/j.ceca.2008.03.002. Epub 2008 Apr 23. Cell Calcium. 2008. PMID: 18436303
-
TRPC1 and ORAI1 channels in colon cancer.Cell Calcium. 2019 Jul;81:59-66. doi: 10.1016/j.ceca.2019.06.003. Epub 2019 Jun 7. Cell Calcium. 2019. PMID: 31203007 Review.
-
STIM-TRP Pathways and Microdomain Organization: Contribution of TRPC1 in Store-Operated Ca2+ Entry: Impact on Ca2+ Signaling and Cell Function.Adv Exp Med Biol. 2017;993:159-188. doi: 10.1007/978-3-319-57732-6_9. Adv Exp Med Biol. 2017. PMID: 28900914 Review.
Cited by
-
Divergence in endothelin-1- and bradykinin-activated store-operated calcium entry in afferent sensory neurons.ASN Neuro. 2015 Apr 13;7(2):1759091415578714. doi: 10.1177/1759091415578714. Print 2015 Mar-Apr. ASN Neuro. 2015. PMID: 25873305 Free PMC article.
-
Transient Receptor Potential Canonical (TRPC) Channels: Then and Now.Cells. 2020 Aug 28;9(9):1983. doi: 10.3390/cells9091983. Cells. 2020. PMID: 32872338 Free PMC article. Review.
-
Orai1 and Orai3 Mediate Store-Operated Calcium Entry Contributing to Neuronal Excitability in Dorsal Root Ganglion Neurons.Front Cell Neurosci. 2017 Dec 19;11:400. doi: 10.3389/fncel.2017.00400. eCollection 2017. Front Cell Neurosci. 2017. PMID: 29311831 Free PMC article.
-
Neuronal Store-Operated Calcium Channels.Mol Neurobiol. 2023 Aug;60(8):4517-4546. doi: 10.1007/s12035-023-03352-5. Epub 2023 Apr 28. Mol Neurobiol. 2023. PMID: 37118324 Review.
-
TRP Channels Role in Pain Associated With Neurodegenerative Diseases.Front Neurosci. 2020 Aug 4;14:782. doi: 10.3389/fnins.2020.00782. eCollection 2020. Front Neurosci. 2020. PMID: 32848557 Free PMC article. Review.
References
-
- Brederson J-D, Kym PR, Szallasi A. Targeting TRP channels for pain relief. Eur J Pharmacol. 2013;716:61–76. - PubMed
-
- Ramsey IS, Delling M, Clapham DE. An introduction to TRP channels. Annu Rev Physiol. 2006;68:619–647. - PubMed
-
- Luo W, Wickramasinghe SR, Savitt JM, Griffin JW, Dawson TM, Ginty DD. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons. Neuron. 2007;54:739–754. - PubMed
-
- Fischer MJ, Mak SW, McNaughton PA. Sensitisation of nociceptors–what are ion channels doing. Open Pain J. 2010;3:82–96.
-
- Coutaux A, Adam F, Willer J-C, Le Bars D. Hyperalgesia and allodynia: peripheral mechanisms. Jt Bone Spine Rev Rhum. 2005;72:359–371. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources