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Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine.
J Biol Chem. 2013 May 03; 288(18):12818-27.JB

Abstract

The sensations of pain, itch, and cold often interact with each other. Pain inhibits itch, whereas cold inhibits both pain and itch. TRPV1 and TRPA1 channels transduce pain and itch, whereas TRPM8 transduces cold. The pruritogen chloroquine (CQ) was reported to excite TRPA1, leading to the sensation of itch. It is unclear how CQ excites and modulates TRPA1(+), TRPV1(+), and TRPM8(+) neurons and thus affects the sensations of pain, itch, and cold. Here, we show that only 43% of CQ-excited dorsal root ganglion neurons expressed TRPA1; as expected, the responses of these neurons were completely prevented by the TRPA1 antagonist HC-030031. The remaining 57% of CQ-excited neurons did not express TRPA1, and excitation was not prevented by either a TRPA1 or TRPV1 antagonist but was prevented by the general transient receptor potential canonical (TRPC) channel blocker BTP2 and the selective TRPC3 inhibitor Pyr3. Furthermore, CQ caused potent sensitization of TRPV1 in 51.9% of TRPV1(+) neurons and concomitant inhibition of TRPM8 in 48.8% of TRPM8(+) dorsal root ganglion neurons. Sensitization of TRPV1 is caused mainly by activation of the phospholipase C-PKC pathway following activation of the CQ receptor MrgprA3. By contrast, inhibition of TRPM8 is caused by a direct action of activated Gαq independent of the phospholipase C pathway. Our data suggest the involvement of the TRPC3 channel acting together with TRPA1 to mediate CQ-induced itch. CQ not only elicits itch by directly exciting itch-encoding neurons but also exerts previously unappreciated widespread actions on pain-, itch-, and cold-sensing neurons, leading to enhanced pain and itch.

Authors+Show Affiliations

Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23508958

Citation

Than, Jonathan Y-X L., et al. "Excitation and Modulation of TRPA1, TRPV1, and TRPM8 Channel-expressing Sensory Neurons By the Pruritogen Chloroquine." The Journal of Biological Chemistry, vol. 288, no. 18, 2013, pp. 12818-27.
Than JY, Li L, Hasan R, et al. Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine. J Biol Chem. 2013;288(18):12818-27.
Than, J. Y., Li, L., Hasan, R., & Zhang, X. (2013). Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine. The Journal of Biological Chemistry, 288(18), 12818-27. https://doi.org/10.1074/jbc.M113.450072
Than JY, et al. Excitation and Modulation of TRPA1, TRPV1, and TRPM8 Channel-expressing Sensory Neurons By the Pruritogen Chloroquine. J Biol Chem. 2013 May 3;288(18):12818-27. PubMed PMID: 23508958.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine. AU - Than,Jonathan Y-X L, AU - Li,Lin, AU - Hasan,Raquibul, AU - Zhang,Xuming, Y1 - 2013/03/18/ PY - 2013/3/20/entrez PY - 2013/3/20/pubmed PY - 2013/7/16/medline KW - Calcium Imaging KW - Chloroquine KW - Electrophysiology KW - G Protein-coupled Receptor (GPCR) KW - Itch KW - Pain KW - Sensory Transduction KW - Signal Transduction KW - TRP Channels SP - 12818 EP - 27 JF - The Journal of biological chemistry JO - J Biol Chem VL - 288 IS - 18 N2 - The sensations of pain, itch, and cold often interact with each other. Pain inhibits itch, whereas cold inhibits both pain and itch. TRPV1 and TRPA1 channels transduce pain and itch, whereas TRPM8 transduces cold. The pruritogen chloroquine (CQ) was reported to excite TRPA1, leading to the sensation of itch. It is unclear how CQ excites and modulates TRPA1(+), TRPV1(+), and TRPM8(+) neurons and thus affects the sensations of pain, itch, and cold. Here, we show that only 43% of CQ-excited dorsal root ganglion neurons expressed TRPA1; as expected, the responses of these neurons were completely prevented by the TRPA1 antagonist HC-030031. The remaining 57% of CQ-excited neurons did not express TRPA1, and excitation was not prevented by either a TRPA1 or TRPV1 antagonist but was prevented by the general transient receptor potential canonical (TRPC) channel blocker BTP2 and the selective TRPC3 inhibitor Pyr3. Furthermore, CQ caused potent sensitization of TRPV1 in 51.9% of TRPV1(+) neurons and concomitant inhibition of TRPM8 in 48.8% of TRPM8(+) dorsal root ganglion neurons. Sensitization of TRPV1 is caused mainly by activation of the phospholipase C-PKC pathway following activation of the CQ receptor MrgprA3. By contrast, inhibition of TRPM8 is caused by a direct action of activated Gαq independent of the phospholipase C pathway. Our data suggest the involvement of the TRPC3 channel acting together with TRPA1 to mediate CQ-induced itch. CQ not only elicits itch by directly exciting itch-encoding neurons but also exerts previously unappreciated widespread actions on pain-, itch-, and cold-sensing neurons, leading to enhanced pain and itch. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/23508958/Excitation_and_modulation_of_TRPA1_TRPV1_and_TRPM8_channel_expressing_sensory_neurons_by_the_pruritogen_chloroquine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)33343-5 DB - PRIME DP - Unbound Medicine ER -