Direct inhibition of the cold-activated TRPM8 ion channel by Gαq

Xuming Zhang; Stephanie Mak; Lin Li; Andres Parra; Bristol Denlinger; Carlos Belmonte; Peter A. McNaughton

doi:10.1038/ncb2529

Direct inhibition of the cold-activated TRPM8 ion channel by Gα_q

Xuming Zhang^*, Stephanie Mak, Lin Li, Andres Parra, Bristol Denlinger, Carlos Belmonte, Peter A. McNaughton

^*Corresponding author for this work

University of Cambridge
Univ Miguel Hernandez, Consejo Superior de Investigaciones Cientificas (CSIC), Universidad Miguel Hernandez de Elche, Consejo Super Invest Cient, Inst Neurociencias Alicante

Research output: Contribution to journal › Article › peer-review

130 Citations (Scopus)

Abstract

Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit G alpha(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of G alpha(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a G alpha(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated G alpha(q) protein, but not G beta gamma, potently inhibits TRPM8 in excised patches. We conclude that G alpha(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.

Original language	English
Pages (from-to)	850-858
Number of pages	20
Journal	Nature Cell Biology
Volume	14
Issue number	8
DOIs	https://doi.org/10.1038/ncb2529
Publication status	Published - Aug 2012

Keywords

LIVING CELLS
G-PROTEINS
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE
PHOSPHOLIPASE-C
ALPHA-SUBUNITS
RECEPTOR
MICE
PHOSPHORYLATION
MEMBRANE
TRPV1

Access to Document

10.1038/ncb2529

Cite this

@article{22173cf5ef2f45cc86df275c0bd52cf5,

title = "Direct inhibition of the cold-activated TRPM8 ion channel by Gαq",

abstract = "Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit G alpha(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of G alpha(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a G alpha(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated G alpha(q) protein, but not G beta gamma, potently inhibits TRPM8 in excised patches. We conclude that G alpha(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.",

keywords = "LIVING CELLS, G-PROTEINS, PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE, PHOSPHOLIPASE-C, ALPHA-SUBUNITS, RECEPTOR, MICE, PHOSPHORYLATION, MEMBRANE, TRPV1",

author = "Xuming Zhang and Stephanie Mak and Lin Li and Andres Parra and Bristol Denlinger and Carlos Belmonte and McNaughton, {Peter A.}",

year = "2012",

month = aug,

doi = "10.1038/ncb2529",

language = "English",

volume = "14",

pages = "850--858",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Research",

number = "8",

}

TY - JOUR

T1 - Direct inhibition of the cold-activated TRPM8 ion channel by Gαq

AU - Zhang, Xuming

AU - Mak, Stephanie

AU - Li, Lin

AU - Parra, Andres

AU - Denlinger, Bristol

AU - Belmonte, Carlos

AU - McNaughton, Peter A.

PY - 2012/8

Y1 - 2012/8

N2 - Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit G alpha(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of G alpha(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a G alpha(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated G alpha(q) protein, but not G beta gamma, potently inhibits TRPM8 in excised patches. We conclude that G alpha(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.

AB - Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit G alpha(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of G alpha(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a G alpha(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated G alpha(q) protein, but not G beta gamma, potently inhibits TRPM8 in excised patches. We conclude that G alpha(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.

KW - LIVING CELLS

KW - G-PROTEINS

KW - PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE

KW - PHOSPHOLIPASE-C

KW - ALPHA-SUBUNITS

KW - RECEPTOR

KW - MICE

KW - PHOSPHORYLATION

KW - MEMBRANE

KW - TRPV1

U2 - 10.1038/ncb2529

DO - 10.1038/ncb2529

M3 - Article

SN - 1465-7392

VL - 14

SP - 850

EP - 858

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -