Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine

Jonathan Y.-X.L. Than, Lin Li, Raquibul Hasan, Xuming Zhang

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)12818-12827
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number18
Early online date18 Mar 2013
DOIs
Publication statusPublished - 3 May 2013

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Chloroquine
Sensory Receptor Cells
Neurons
Modulation
Pain
Spinal Ganglia
Type C Phospholipases
Chemical activation
Transient Receptor Potential Channels

Keywords

  • acetanilides
  • amebicides
  • anilides
  • Gq-G11
  • chloroquine
  • GTP-binding protein alpha subunits
  • spinal ganglia
  • HEK293 cells
  • purines
  • pyrazoles
  • sensation
  • sensory receptor cells
  • TRPM cation channels
  • TRPV cation channels
  • thiadiazoles
  • transient receptor potential channels
  • type C phospholipases

Cite this

@article{9a42d3db23314a80aa29bbd3d5447901,
title = "Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine",
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.",
keywords = "acetanilides, amebicides, anilides, Gq-G11, chloroquine, GTP-binding protein alpha subunits, spinal ganglia, HEK293 cells, purines, pyrazoles, sensation, sensory receptor cells, TRPM cation channels, TRPV cation channels, thiadiazoles, transient receptor potential channels, type C phospholipases",
author = "Than, {Jonathan Y.-X.L.} and Lin Li and Raquibul Hasan and Xuming Zhang",
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Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine. / Than, Jonathan Y.-X.L.; Li, Lin; Hasan, Raquibul; Zhang, Xuming.

In: Journal of Biological Chemistry, Vol. 288, No. 18, 03.05.2013, p. 12818-12827.

Research output: Contribution to journalArticle

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

PY - 2013/5/3

Y1 - 2013/5/3

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.

AB - 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.

KW - acetanilides

KW - amebicides

KW - anilides

KW - Gq-G11

KW - chloroquine

KW - GTP-binding protein alpha subunits

KW - spinal ganglia

KW - HEK293 cells

KW - purines

KW - pyrazoles

KW - sensation

KW - sensory receptor cells

KW - TRPM cation channels

KW - TRPV cation channels

KW - thiadiazoles

KW - transient receptor potential channels

KW - type C phospholipases

UR - http://www.jbc.org/content/288/18/12818

U2 - 10.1074/jbc.M113.450072

DO - 10.1074/jbc.M113.450072

M3 - Article

VL - 288

SP - 12818

EP - 12827

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 18

ER -