Calmodulin is responsible for Ca2+-dependent regulation of TRPA1 channels

Raquibul Hasan, Alasdair T.S. Leeson-Payne, Jonathan H. Jaggar, Xuming Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

TRPA1 is a Ca2+-permeable ion channel involved in many sensory disorders such as pain, itch and neuropathy. Notably, the function of TRPA1 depends on Ca2+, with low Ca2+ potentiating and high Ca2+ inactivating TRPA1. However, it remains unknown how Ca2+ exerts such contrasting effects. Here, we show that Ca2+ regulates TRPA1 through calmodulin, which binds to TRPA1 in a Ca2+-dependent manner. Calmodulin binding enhanced TRPA1 sensitivity and Ca2+-evoked potentiation of TRPA1 at low Ca2+, but inhibited TRPA1 sensitivity and promoted TRPA1 desensitization at high Ca2+. Ca2+-dependent potentiation and inactivation of TRPA1 were selectively prevented by disrupting the interaction of the carboxy-lobe of calmodulin with a calmodulin-binding domain in the C-terminus of TRPA1. Calmodulin is thus a critical Ca2+ sensor enabling TRPA1 to respond to diverse Ca2+ signals distinctly.
Original languageEnglish
Article number45098
Number of pages12
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 23 Mar 2017

Fingerprint

Calmodulin
Sensation Disorders
Ion Channels
Pain

Bibliographical note

© The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Funding: Islamic Development Bank and the Cambridge Commonwealth
Trust; BBSRC EastBio Ph.D studentship; MRC new investigator research grant; and Royal Society.

Keywords

  • Ion channels in the nervous system
  • Somatic system

Cite this

Hasan, Raquibul ; Leeson-Payne, Alasdair T.S. ; Jaggar, Jonathan H. ; Zhang, Xuming. / Calmodulin is responsible for Ca2+-dependent regulation of TRPA1 channels. In: Scientific Reports. 2017 ; Vol. 7.
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Calmodulin is responsible for Ca2+-dependent regulation of TRPA1 channels. / Hasan, Raquibul; Leeson-Payne, Alasdair T.S.; Jaggar, Jonathan H.; Zhang, Xuming.

In: Scientific Reports, Vol. 7, 45098, 23.03.2017.

Research output: Contribution to journalArticle

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AU - Zhang, Xuming

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N2 - TRPA1 is a Ca2+-permeable ion channel involved in many sensory disorders such as pain, itch and neuropathy. Notably, the function of TRPA1 depends on Ca2+, with low Ca2+ potentiating and high Ca2+ inactivating TRPA1. However, it remains unknown how Ca2+ exerts such contrasting effects. Here, we show that Ca2+ regulates TRPA1 through calmodulin, which binds to TRPA1 in a Ca2+-dependent manner. Calmodulin binding enhanced TRPA1 sensitivity and Ca2+-evoked potentiation of TRPA1 at low Ca2+, but inhibited TRPA1 sensitivity and promoted TRPA1 desensitization at high Ca2+. Ca2+-dependent potentiation and inactivation of TRPA1 were selectively prevented by disrupting the interaction of the carboxy-lobe of calmodulin with a calmodulin-binding domain in the C-terminus of TRPA1. Calmodulin is thus a critical Ca2+ sensor enabling TRPA1 to respond to diverse Ca2+ signals distinctly.

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