Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain.
Moparthi, Lavanya LU ; Survery, Sabeen LU ; Kreir, Mohamed ; Simonsen, Charlotte LU ; Kjellbom, Per LU ; Högestätt, Edward LU ; Johanson, Urban LU
and Zygmunt, Peter
LU
(2014)
In Proceedings of the National Academy of Sciences
111(47).
p.16901-16906
- Abstract
- We have purified and reconstituted human transient receptor potential (TRP) subtype A1 (hTRPA1) into lipid bilayers and recorded single-channel currents to understand its inherent thermo- and chemosensory properties as well as the role of the ankyrin repeat domain (ARD) of the N terminus in channel behavior. We report that hTRPA1 with and without its N-terminal ARD (Δ1-688 hTRPA1) is intrinsically cold-sensitive, and thus, cold-sensing properties of hTRPA1 reside outside the N-terminal ARD. We show activation of hTRPA1 by the thiol oxidant 2-((biotinoyl)amino)ethyl methanethiosulfonate (MTSEA-biotin) and that electrophilic compounds activate hTRPA1 in the presence and absence of the N-terminal ARD. The nonelectrophilic compounds menthol... (More)
- We have purified and reconstituted human transient receptor potential (TRP) subtype A1 (hTRPA1) into lipid bilayers and recorded single-channel currents to understand its inherent thermo- and chemosensory properties as well as the role of the ankyrin repeat domain (ARD) of the N terminus in channel behavior. We report that hTRPA1 with and without its N-terminal ARD (Δ1-688 hTRPA1) is intrinsically cold-sensitive, and thus, cold-sensing properties of hTRPA1 reside outside the N-terminal ARD. We show activation of hTRPA1 by the thiol oxidant 2-((biotinoyl)amino)ethyl methanethiosulfonate (MTSEA-biotin) and that electrophilic compounds activate hTRPA1 in the presence and absence of the N-terminal ARD. The nonelectrophilic compounds menthol and the cannabinoid Δ(9)-tetrahydrocannabiorcol (C16) directly activate hTRPA1 at different sites independent of the N-terminal ARD. The TRPA1 antagonist HC030031 inhibited cold and chemical activation of hTRPA1 and Δ1-688 hTRPA1, supporting a direct interaction with hTRPA1 outside the N-terminal ARD. These findings show that hTRPA1 is an intrinsically cold- and chemosensitive ion channel. Thus, second messengers, including Ca(2+), or accessory proteins are not needed for hTRPA1 responses to cold or chemical activators. We suggest that conformational changes outside the N-terminal ARD by cold, electrophiles, and nonelectrophiles are important in hTRPA1 channel gating and that targeting chemical interaction sites outside the N-terminal ARD provides possibilities to fine tune TRPA1-based drug therapies (e.g., for treatment of pain associated with cold hypersensitivity and cardiovascular disease). (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4816853
- author
- Moparthi, Lavanya
LU
; Survery, Sabeen
LU
; Kreir, Mohamed
; Simonsen, Charlotte
LU
; Kjellbom, Per
LU
; Högestätt, Edward
LU
; Johanson, Urban
LU
and Zygmunt, Peter
LU
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Proceedings of the National Academy of Sciences
- volume
- 111
- issue
- 47
- pages
- 16901 - 16906
- publisher
- National Academy of Sciences
- external identifiers
-
- pmid:25389312
- wos:000345662700061
- scopus:84912567148
- pmid:25389312
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.1412689111
- language
- English
- LU publication?
- yes
- id
- 526b495a-488e-4b52-941e-bb50f17f8243 (old id 4816853)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/25389312?dopt=Abstract
- date added to LUP
- 2016-04-01 09:53:18
- date last changed
- 2022-04-11 23:45:19
@article{526b495a-488e-4b52-941e-bb50f17f8243,
abstract = {{We have purified and reconstituted human transient receptor potential (TRP) subtype A1 (hTRPA1) into lipid bilayers and recorded single-channel currents to understand its inherent thermo- and chemosensory properties as well as the role of the ankyrin repeat domain (ARD) of the N terminus in channel behavior. We report that hTRPA1 with and without its N-terminal ARD (Δ1-688 hTRPA1) is intrinsically cold-sensitive, and thus, cold-sensing properties of hTRPA1 reside outside the N-terminal ARD. We show activation of hTRPA1 by the thiol oxidant 2-((biotinoyl)amino)ethyl methanethiosulfonate (MTSEA-biotin) and that electrophilic compounds activate hTRPA1 in the presence and absence of the N-terminal ARD. The nonelectrophilic compounds menthol and the cannabinoid Δ(9)-tetrahydrocannabiorcol (C16) directly activate hTRPA1 at different sites independent of the N-terminal ARD. The TRPA1 antagonist HC030031 inhibited cold and chemical activation of hTRPA1 and Δ1-688 hTRPA1, supporting a direct interaction with hTRPA1 outside the N-terminal ARD. These findings show that hTRPA1 is an intrinsically cold- and chemosensitive ion channel. Thus, second messengers, including Ca(2+), or accessory proteins are not needed for hTRPA1 responses to cold or chemical activators. We suggest that conformational changes outside the N-terminal ARD by cold, electrophiles, and nonelectrophiles are important in hTRPA1 channel gating and that targeting chemical interaction sites outside the N-terminal ARD provides possibilities to fine tune TRPA1-based drug therapies (e.g., for treatment of pain associated with cold hypersensitivity and cardiovascular disease).}},
author = {{Moparthi, Lavanya and Survery, Sabeen and Kreir, Mohamed and Simonsen, Charlotte and Kjellbom, Per and Högestätt, Edward and Johanson, Urban and Zygmunt, Peter}},
issn = {{1091-6490}},
language = {{eng}},
number = {{47}},
pages = {{16901--16906}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences}},
title = {{Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain.}},
url = {{http://dx.doi.org/10.1073/pnas.1412689111}},
doi = {{10.1073/pnas.1412689111}},
volume = {{111}},
year = {{2014}},
}