Agonist-Dependent Modulation of Cell Surface Expression of the Cold Receptor TRPM8

Previous research identified TRPM8 and TRPA1 cold transducers with separate functions, one being functional in the non-noxious range and the second one being a nociceptive transducer. TRPM8-deficient mice present overt deficits in the detection of environmental cool, but not a lack of cold avoidance and TRPA1-deficient mice show clear deficits in some cold nocifensive assays. The extent of TRPA1's contribution to cold sensing in vivo is still unclear, because mice lacking both TRPM8 and TRPA1 (DKO) were described with unchanged cold avoidance from TRPM8−/− based on a two-temperature-choice assay and by c-fos measurement. The present study was designed to differentiate how much TRPM8 alone and combined TRPA1 and TRPM8 contribute to cold sensing. We analyzed behavior in the thermal ring track assay adjusted between 30 and 5°C and found a large reduction in cold avoidance of the double knockout mice as compared to the TRPM8-deficient mice. We also revisited skin-nerve recordings from saphenous-nerve skin preparations with regard to nociceptors and thermoreceptors. We compared the frequency and characteristics of the cold responses of TRPM8-expressing and TRPM8-negative C-fiber nociceptors in C57BL/6J mice with nociceptors of TRPM8-deficient and DKO mice and found that TRPM8 enables nociceptors to encode cold temperatures with higher firing rates and larger responses with sustained, static component. In TRPM8−/−, C-fiber cold nociceptors were markedly reduced and appeared further reduced in DKO. Nevertheless, the remaining cold responses in both knockout strains were similar in their characteristics and they were indifferent from the TRPM8-negative cold responses found in C57BL/6J mice. TRPM8 had a comparably essential role for encoding cold in thermoreceptors and lack of TRPM8 reduced response magnitude, peak and mean firing rates and the incidence of thermoreceptors. The encoding deficits were similar in the DKO strain. Our data illustrate that lack of TRPA1 in TRPM8-deficient mice results in a disproportionately large reduction in cold avoidance behavior and also affects the incidence of cold encoding fiber types. Presumably TRPA1 compensates for lack of TRPM8 to a certain extent and both channels cooperate to cover the entire cold temperature range, making cold-temperature encoding by TRPA1—although less powerful—synergistic to TRPM8.

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“…In C57BL/6J and TRPM8 −/− some recordings were included from a previous publication (Toro et al, 2015); All values are mean ± SD .…”

Section: Resultsmentioning

confidence: 99%

Cold Temperature Encoding by Cutaneous TRPA1 and TRPM8-Carrying Fibers in the Mouse

Winter

Gruschwitz

Eger

et al. 2017

Front. Mol. Neurosci.

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“…Other selective TRP as well as Na + or K + channel modulators remain in the pre-clinical development stage where their efficacy, selectivity, and dose in vitro and in vivo remain a topic of investigation. Additional strategies to treat cold pain may include tonic cross-inhibition of cold-responsive spinal neurons through modulation of CGRPa-expressing pathways [185] or trafficking of cold-sensitive TRP channels via regulation of SNARE-dependent exocytosis [186]. Thus, promising new approaches to the treatment of cold pain are on the horizon.…”

Section: Treatment Of Pathological Cold Painmentioning

confidence: 99%

Therapeutic opportunities for targeting cold pain pathways

Yin

Zimmermann

Vetter

et al. 2015

Biochemical Pharmacology

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Please cite this article as: Yin K, Zimmermann K, Vetter I, Lewis RJ, Therapeutic opportunities for targeting cold pain pathways, Biochemical Pharmacology (2014), http://dx.doi. org/10.1016/j.bcp.2014.09.024 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…In recent years, important advances have been made in our knowledge about the biophysical properties of TRPM8 1 . However, the knowledge about the trafficking mechanism that determine the abundance of TRPM8 at the plasma membrane is very sparse 4 . Nevertheless, modulation of the number of active cold sensitive TRPM8 channels at the plasma membrane represents an important regulatory mechanism under normal and pathophysiological conditions.…”

mentioning

confidence: 99%

A cellular pathway controlling functional plasma membrane incorporation of the cold sensor TRPM8

Vriens

Voets

2016

Temperature

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Agonist-Dependent Modulation of Cell Surface Expression of the Cold Receptor TRPM8

Cited by 25 publications

References 52 publications

Cold Temperature Encoding by Cutaneous TRPA1 and TRPM8-Carrying Fibers in the Mouse

Cold Temperature Encoding by Cutaneous TRPA1 and TRPM8-Carrying Fibers in the Mouse

Therapeutic opportunities for targeting cold pain pathways

A cellular pathway controlling functional plasma membrane incorporation of the cold sensor TRPM8

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