Odontoblast TRPC5 channels signal cold pain in teeth.

[en] Teeth are composed of many tissues, covered by an inflexible and obdurate enamel. Unlike most other tissues, teeth become extremely cold sensitive when inflamed. The mechanisms of this cold sensation are not understood. Here, we clarify the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold sensing. The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing via TRPC5's relative sensitivity to intracellular calcium and lack of desensitization. Our data provide concrete functional evidence that equipping odontoblasts with the cold-sensor TRPC5 expands traditional odontoblast functions and renders it a previously unknown integral cellular component of the dental cold sensing system.

Disciplines :

Anatomy (cytology, histology, embryology...) & physiology

Author, co-author :

Bernal, Laura

Sotelo-Hitschfeld, Pamela

König, Christine

Sinica, Viktor

Wyatt, Amanda

Winter, Zoltan

Hein, Alexander

Touska, Filip

Reinhardt, Susanne

Tragl, Aaron

More authors (14 more)

Language :

English

Title :

Odontoblast TRPC5 channels signal cold pain in teeth.

Publication date :

2021

Journal title :

Science Advances

eISSN :

2375-2548

Publisher :

American Association for the Advancement of Science (AAAS), Washington, United States - District of Columbia

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Available on ORBi :

since 12 May 2021

Statistics

Number of views

67 (6 by ULiège)

Number of downloads

4 (4 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

N. J. Kassebaum, E. Bernabé, M. Dahiya, B. Bhandari, C. J. L. Murray, W. Marcenes, Global burden of untreated caries: A systematic review and metaregression. J. Dent. Res. 94, 650–658 (2015).
R. A. Alghaithy, A. J. E. Qualtrough, Pulp sensibility and vitality tests for diagnosing pulpal health in permanent teeth: A critical review. Int. Endod. J. 50, 135–142 (2017).
M. Lin, G. M. Genin, F. Xu, T. Lu, Thermal pain in teeth: Electrophysiology governed by thermomechanics. Appl. Mech. Rev. 66, 0308011–3080114 (2014).
M. Brännström, G. Johnson, Movements of the dentine and pulp liquids on application of thermal stimuli. An in vitro study. Acta Odontol. Scand. 28, 59–70 (1970).
J. Vriens, B. Nilius, T. Voets, Peripheral thermosensation in mammals. Nat. Rev. Neurosci. 15, 573–589 (2014).
Z. Winter, P. Gruschwitz, S. Eger, F. Touska, K. Zimmermann, Cold temperature encoding by cutaneous TRPA1 and TRPM8-carrying fibers in the mouse. Front. Mol. Neurosci. 10, 209 (2017).
A. Kadala, P. Sotelo-Hitschfeld, Z. Ahmad, P. Tripal, B. Schmid, A. Mueller, L. Bernal, Z. Winter, S. Brauchi, U. Lohbauer, K. Messlinger, J. K. Lennerz, K. Zimmermann, Fluorescent labeling and 2-photon imaging of mouse tooth pulp nociceptors. J. Dent. Res. 97, 460–466 (2018).
Y. S. Kim, T. H. Kim, D. D. McKemy, Y. C. Bae, Expression of vesicular glutamate transporters in transient receptor potential melastatin 8 (TRPM8)-positive dental afferents in the mouse. Neuroscience 303, 378–388 (2015).
Y. S. Kim, H. K. Jung, T. K. Kwon, C. S. Kim, J. H. Cho, D. K. Ahn, Y. C. Bae, Expression of transient receptor potential ankyrin 1 in human dental pulp. J. Endod. 38, 1087–1092 (2012).
I. A. El Karim, G. J. Linden, T. M. Curtis, I. About, M. K. McGahon, C. R. Irwin, F. T. Lundy, Human odontoblasts express functional thermo-sensitive TRP channels: Implications for dentin sensitivity. Pain 152, 2211–2223 (2011).
I. A. El Karim, G. J. Linden, T. M. Curtis, I. About, M. K. McGahon, C. R. Irwin, S. A. Killough, F. T. Lundy, Human dental pulp fibroblasts express the “cold-sensing” transient receptor potential channels TRPA1 and TRPM8. J. Endod. 37, 473–478 (2011).
K. Tazawa, H. Ikeda, N. Kawashima, T. Okiji, Transient receptor potential melastatin (TRPM) 8 is expressed in freshly isolated native human odontoblasts. Arch. Oral Biol. 75, 55–61 (2017).
O. Egbuniwe, S. Grover, A. K. Duggal, A. Mavroudis, M. Yazdi, T. Renton, L. Di Silvio, A. D. Grant, TRPA1 and TRPV4 activation in human odontoblasts stimulates ATP release. J. Dent. Res. 93, 911–917 (2014).
K. Y. Yeon, G. Chung, M. S. Shin, S. J. Jung, J. S. Kim, S. B. Oh, Adult rat odontoblasts lack noxious thermal sensitivity. J. Dent. Res. 88, 328–332 (2009).
M. Tsumura, U. Sobhan, M. Sato, M. Shimada, A. Nishiyama, A. Kawaguchi, M. Soya, H. Kuroda, M. Tazaki, Y. Shibukawa, Functional expression of TRPM8 and TRPA1 channels in rat odontoblasts. PLOS ONE 8, e82233 (2013).
B. Michot, C. S. Lee, J. L. Gibbs, TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold. Sci. Rep. 8, 13198 (2018).
K. Zimmermann, J. K. Lennerz, A. Hein, A. S. Link, J. S. Kaczmarek, M. Delling, S. Uysal, J. D. Pfeifer, A. Riccio, D. E. Clapham, Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system. Proc. Natl. Acad. Sci. U.S.A. 108, 18114–18119 (2011).
J. L. Gibbs, R. Urban, A. I. Basbaum, Paradoxical surrogate markers of dental injury-induced pain in the mouse. Pain 154, 1358–1367 (2013).
K. Zimmermann, A. Hein, U. Hager, J. S. Kaczmarek, B. P. Turnquist, D. E. Clapham, P. W. Reeh, Phenotyping sensory nerve endings in vitro in the mouse. Nat. Protoc. 4, 174–196 (2009).
T. Memon, K. Chase, L. S. Leavitt, B. M. Olivera, R. W. Teichert, TRPA1 expression levels and excitability brake by KV channels influence cold sensitivity of TRPA1-expressing neurons. Neuroscience 353, 76–86 (2017).
Y. Schwarz, K. Oleinikov, B. Schindeldecker, A. Wyatt, P. Weißgerber, V. Flockerzi, U. Boehm, M. Freichel, D. Bruns, TRPC channels regulate Ca2+-signaling and short-term plasticity of fast glutamatergic synapses. PLOS Biol. 17, e3000445 (2019).
L. T. Alvarado, G. M. Perry, K. M. Hargreaves, M. A. Henry, TRPM8 Axonal expression is decreased in painful human teeth with irreversible pulpitis and cold hyperalgesia. J. Endod. 33, 1167–1171 (2007).
M. R. Byers, R. E. Westenbroek, Odontoblasts in developing, mature and ageing rat teeth have multiple phenotypes that variably express all nine voltage-gated sodium channels. Arch. Oral Biol. 56, 1199–1220 (2011).
A. Tanaka, Y. Shibukawa, M. Yamamoto, S. Abe, H. Yamamoto, S. Shintani, Developmental studies on the acquisition of perception conducting pathways via TRP channels in rat molar odontoblasts using immunohistochemistry and RT-qPCR. Anat. Sci. Int. 95, 251–257 (2020).
T. Gunji, Morphological research on the sensitivity of dentin. Arch. Histol. Jpn. 45, 45–67 (1982).
C. F. Cox, K. Suzuki, H. Yamaguchi, J. D. Ruby, S. Suzuki, N. Akimoto, N. Maeda, Y. Momoi, Sensory mechanisms in dentine: A literature review of light microscopy (LM), transmission microscopy (TEM), scanning microscopy (SEM) & electro physiological (EP) tooth sensitivity: Is the ciliary organelle on the odontoblast the elusive primary nociceptor? Dent. Oral Craniofacial Res. 4, 1–14 (2017).
N. Vongsavan, B. Matthews, The relationship between the discharge of intradental nerves and the rate of fluid flow through dentine in the cat. Arch. Oral Biol. 52, 640–647 (2007).
H. O. Trowbridge, M. Franks, E. Korostoff, R. Emling, Sensory response to thermal stimulation in human teeth. J. Endod. 6, 405–412 (1980).
P. Linsuwanont, J. E. Palamara, H. H. Messer, An investigation of thermal stimulation in intact teeth. Arch. Oral Biol. 52, 218–227 (2007).
W. Chidchuangchai, N. Vongsavan, B. Matthews, Sensory transduction mechanisms responsible for pain caused by cold stimulation of dentine in man. Arch. Oral Biol. 52, 154–160 (2007).
K. B. Muzzin, R. Johnson, Effects of potassium oxalate on dentin hypersensitivity in vivo. J. Periodontol. 60, 151–158 (1989).
O. Ajcharanukul, W. Chidchuangchai, P. Charoenlarp, N. Vongsavan, B. Matthews, Sensory transduction in human teeth with inflamed pulps. J. Dent. Res. 90, 678–682 (2011).
H. Magloire, M. L. Couble, B. Thivichon-Prince, J. C. Maurin, F. Bleicher, Odontoblast: A mechano-sensory cell. J. Exp. Zool. B Mol. Dev. Evol. 312B, 416–424 (2009).
Y. A. Nikolaev, C. D. Cox, P. Ridone, P. R. Rohde, J. F. Cordero-Morales, V. Vasquez, D. R. Laver, B. Martinac, Mammalian TRP ion channels are insensitive to membrane stretch. J. Cell Sci. 132, jcs238360 (2019).
L. Moparthi, P. M. Zygmunt, Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel. Cell Calcium 91, 102255 (2020).
A. G. Obukhov, M. C. Nowycky, TRPC5 activation kinetics are modulated by the scaffolding protein ezrin/radixin/moesin-binding phosphoprotein-50 (EBP50). J. Cell. Physiol. 201, 227–235 (2004).
A. Gomis, S. Soriano, C. Belmonte, F. Viana, Hypoosmotic- and pressure-induced membrane stretch activate TRPC5 channels. J. Physiol. 586, 5633–5649 (2008).
B. Allard, H. Magloire, M. L. Couble, J. C. Maurin, F. Bleicher, Voltage-gated sodium channels confer excitability to human odontoblasts: Possible role in tooth pain transmission. J. Biol. Chem. 281, 29002–29010 (2006).
M. R. Byers, Dental sensory receptors. Int. Rev. Neurobiol. 25, 39–94 (1984).
H. Ikeda, H. Suda, Odontoblastic syncytium through electrical coupling in the human dental pulp. J. Dent. Res. 92, 371–375 (2013).
Y. S. Cho, C. H. Ryu, J. H. Won, H. Vang, S. B. Oh, J. Y. Ro, Y. C. Bae, Rat odontoblasts may use glutamate to signal dentin injury. Neuroscience 335, 54–63 (2016).
N. T. Blair, J. S. Kaczmarek, D. E. Clapham, Intracellular calcium strongly potentiates agonist-activated TRPC5 channels. J. Gen. Physiol. 133, 525–546 (2009).
P. R. Lee, J. Y. Lee, H. B. Kim, J. H. Lee, S. B. Oh, TRPM8 mediates hyperosmotic stimuli-induced nociception in dental afferents. J. Dent. Res. 99, 107–114 (2019).
S. Yamamoto, N. Takahashi, Y. Mori, Chemical physiology of oxidative stress-activated TRPM2 and TRPC5 channels. Prog. Biophys. Mol. Biol. 103, 18–27 (2010).
E. K. Curtis, In pursuit of palliation: Oil of cloves in the art of dentistry. Bull. Hist. Dent. 38, 9–14 (1990).
P. W. Lucas, S. M. Philip, D. Al-Qeoud, N. Al-Draihim, S. Saji, A. van Casteren, Structure and scale of the mechanics of mammalian dental enamel viewed from an evolutionary perspective. Evol. Dev. 18, 54–61 (2016).
K. Y. Kwan, A. J. Allchorne, M. A. Vollrath, A. P. Christensen, D. S. Zhang, C. J. Woolf, D. P. Corey, TRPA1 contributes to cold, mechanical, and chemical Nociception but is not essential for hair-cell transduction. Neuron 50, 277–289 (2006).
A. Dhaka, A. N. Murray, J. Mathur, T. J. Earley, M. J. Petrus, A. Patapoutian, TRPM8 is required for cold sensation in mice. Neuron 54, 371–378 (2007).
T. Xue, M. T. H. Do, A. Riccio, Z. Jiang, J. Hsieh, H. C. Wang, S. L. Merbs, D. S. Welsbie, T. Yoshioka, P. Weissgerber, S. Stolz, V. Flockerzi, M. Freichel, M. I. Simon, D. E. Clapham, K.-W. Yau, Melanopsin signalling in mammalian iris and retina. Nature 479, 67–73 (2011).
I. Vetter, A. Hein, S. Sattler, S. Hessler, F. Touska, E. Bressan, A. Parra, U. Hager, A. Leffler, S. Boukalova, M. Nissen, R. J. Lewis, C. Belmonte, C. Alzheimer, T. Huth, V. Vlachova, P. W. Reeh, K. Zimmermann, Amplified cold transduction in native nociceptors by M-channel inhibition. J. Neurosci. 33, 16627–16641 (2013).
I. Vetter, F. Touska, A. Hess, R. Hinsbey, S. Sattler, A. Lampert, M. Sergejeva, A. Sharov, L. S. Collins, M. Eberhardt, M. Engel, P. J. Cabot, J. N. Wood, V. Vlachova, P. W. Reeh, R. J. Lewis, K. Zimmermann, Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling. EMBO J. 31, 3795–3808 (2012).
A. Wyatt, P. Wartenberg, M. Candlish, G. Krasteva-Christ, V. Flockerzi, U. Boehm, Genetic strategies to analyze primary TRP channel-expressing cells in mice. Cell Calcium 67, 91–104 (2017).
C. I. Rodriguez, F. Buchholz, J. Galloway, R. Sequerra, J. Kasper, R. Ayala, A. F. Stewart, S. M. Dymecki, High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP. Nat. Genet. 25, 139–140 (2000).
S. Wen, I. N. Götze, O. Mai, C. Schauer, T. Leinders-Zufall, U. Boehm, Genetic identification of GnRH receptor neurons: A new model for studying neural circuits underlying reproductive physiology in the mouse brain. Endocrinology 152, 1515–1526 (2011).
D. C. Hoaglin, B. Iglewicz, Fine-tuning some resistant rules for outlier labeling. J. Am. Stat. Assoc. 82, 1147–1149 (1987).
C. Roza, J. A. Lopez-Garcia, Retigabine, the specific KCNQ channel opener, blocks ectopic discharges in axotomized sensory fibres. Pain 138, 537–545 (2008).
Y. Matsubayashi, L. Iwai, H. Kawasaki, Fluorescent double-labeling with carbocyanine neuronal tracing and immunohistochemistry using a cholesterol-specific detergent digitonin. J. Neurosci. Methods 174, 71–81 (2008).
K. N. Natarajan, Z. Miao, M. Jiang, X. Huang, H. Zhou, J. Xie, C. Wang, S. Qin, Z. Zhao, L. Wu, N. Yang, B. Li, Y. Hou, S. Liu, S. A. Teichmann, Comparative analysis of sequencing technologies for single-cell transcriptomics. Genome Biol. 20, 70 (2019).
S. Picelli, A. K. Björklund, O. R. Faridani, S. Sagasser, G. Winberg, R. Sandberg, Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat. Methods 10, 1096–1098 (2013).
T. D. Wu, S. Nacu, Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 26, 873–881 (2010).
Y. Liao, G. K. Smyth, W. Shi, featureCounts: An efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
B. Schmid, P. Tripal, T. Fraass, C. Kersten, B. Ruder, A. Gruneboom, J. Huisken, R. Palmisano, 3Dscript: Animating 3D/4D microscopy data using a natural-language-based syntax. Nat. Methods 16, 278–280 (2019).
M. P. Whyte, W. H. McAlister, D. V. Novack, K. L. Clements, P. L. Schoenecker, D. Wenkert, Bisphosphonate-induced osteopetrosis: Novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases. J. Bone Miner. Res. 23, 1698–1707 (2008).
J. K. Lennerz, V. Ruhle, E. P. Ceppa, W. L. Neuhuber, N. W. Bunnett, E. F. Grady, K. Messlinger, Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: Differences between peripheral and central CGRP receptor distribution. J. Comp. Neurol. 507, 1277–1299 (2008).
R. A. Colby, Color Atlas of Oral Pathology; Histology and Embryology, Developmental Disturbances, Diseases of the Teeth and Supporting Structures, Diseases of the Oral Mucosa and Jaws, Neoplasms (Lippincott Williams & Wilkins, 1961).
N. N. Shuhaibar, A. R. Hand, M. Terasaki, Odontoblast processes of the mouse incisor are plates oriented in the direction of growth. Anat. Rec. (Hoboken), 1–8 (2020).