Cargando…
Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans
Multiple genome-wide association studies have identified non-coding single-nucleotide variants (SNVs) near (e.g., rs10166942[C]) or within (rs17862920[T]) the TRPM8 gene that encodes a cold thermosensor is associated with reduced migraine risk. Furthermore, rs10166942[C]) and rs10166942[T]) are more...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927963/ https://www.ncbi.nlm.nih.gov/pubmed/31873179 http://dx.doi.org/10.1038/s41598-019-56295-0 |
_version_ | 1783482377232711680 |
---|---|
author | Gavva, Narender R. Sandrock, Robert Arnold, Gregory E. Davis, Michael Lamas, Edwin Lindvay, Chris Li, Chi-Ming Smith, Brian Backonja, Miroslav Gabriel, Kristin Vargas, Gabriel |
author_facet | Gavva, Narender R. Sandrock, Robert Arnold, Gregory E. Davis, Michael Lamas, Edwin Lindvay, Chris Li, Chi-Ming Smith, Brian Backonja, Miroslav Gabriel, Kristin Vargas, Gabriel |
author_sort | Gavva, Narender R. |
collection | PubMed |
description | Multiple genome-wide association studies have identified non-coding single-nucleotide variants (SNVs) near (e.g., rs10166942[C]) or within (rs17862920[T]) the TRPM8 gene that encodes a cold thermosensor is associated with reduced migraine risk. Furthermore, rs10166942[C]) and rs10166942[T]) are more prevalent in populations that reside in hotter and colder climates, respectively. Here we assessed whether these alleles affect TRPM8 expression in humans and human physiologic responses to cold challenge. Here we show that TRPM8 expression is decreased from the chromosome harboring the rs10166942[C] allele in the human dorsal root ganglia. Moreover, carriers of rs10166942[C] required significantly lower temperatures and longer duration of exposure to reach a cold pain threshold (CPTh), which correlated with decreased TRPM8 expression expected in the carriers. This study provides evidence for a genotype-dependent influence on cold pain sensation suggesting that carriers of the reduced migraine risk allele have reduced sensitivity to cold stimuli and that TRPM8 acts as a cold thermosensor and cold pain transducer in humans. Reduced TRPM8 expression and function underpins the migraine protection in carriers of rs10166942[C]; thus, the evaluation of TRPM8 antagonists as migraine therapeutics is warranted. Furthermore, these results provide mechanistic insights for evolutionary positive selection of rs10166942[T] allele in adaptation along latitudinal cline to colder climates. |
format | Online Article Text |
id | pubmed-6927963 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69279632019-12-27 Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans Gavva, Narender R. Sandrock, Robert Arnold, Gregory E. Davis, Michael Lamas, Edwin Lindvay, Chris Li, Chi-Ming Smith, Brian Backonja, Miroslav Gabriel, Kristin Vargas, Gabriel Sci Rep Article Multiple genome-wide association studies have identified non-coding single-nucleotide variants (SNVs) near (e.g., rs10166942[C]) or within (rs17862920[T]) the TRPM8 gene that encodes a cold thermosensor is associated with reduced migraine risk. Furthermore, rs10166942[C]) and rs10166942[T]) are more prevalent in populations that reside in hotter and colder climates, respectively. Here we assessed whether these alleles affect TRPM8 expression in humans and human physiologic responses to cold challenge. Here we show that TRPM8 expression is decreased from the chromosome harboring the rs10166942[C] allele in the human dorsal root ganglia. Moreover, carriers of rs10166942[C] required significantly lower temperatures and longer duration of exposure to reach a cold pain threshold (CPTh), which correlated with decreased TRPM8 expression expected in the carriers. This study provides evidence for a genotype-dependent influence on cold pain sensation suggesting that carriers of the reduced migraine risk allele have reduced sensitivity to cold stimuli and that TRPM8 acts as a cold thermosensor and cold pain transducer in humans. Reduced TRPM8 expression and function underpins the migraine protection in carriers of rs10166942[C]; thus, the evaluation of TRPM8 antagonists as migraine therapeutics is warranted. Furthermore, these results provide mechanistic insights for evolutionary positive selection of rs10166942[T] allele in adaptation along latitudinal cline to colder climates. Nature Publishing Group UK 2019-12-23 /pmc/articles/PMC6927963/ /pubmed/31873179 http://dx.doi.org/10.1038/s41598-019-56295-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gavva, Narender R. Sandrock, Robert Arnold, Gregory E. Davis, Michael Lamas, Edwin Lindvay, Chris Li, Chi-Ming Smith, Brian Backonja, Miroslav Gabriel, Kristin Vargas, Gabriel Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans |
title | Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans |
title_full | Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans |
title_fullStr | Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans |
title_full_unstemmed | Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans |
title_short | Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans |
title_sort | reduced trpm8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927963/ https://www.ncbi.nlm.nih.gov/pubmed/31873179 http://dx.doi.org/10.1038/s41598-019-56295-0 |
work_keys_str_mv | AT gavvanarenderr reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT sandrockrobert reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT arnoldgregorye reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT davismichael reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT lamasedwin reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT lindvaychris reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT lichiming reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT smithbrian reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT backonjamiroslav reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT gabrielkristin reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans AT vargasgabriel reducedtrpm8expressionunderpinsreducedmigraineriskandattenuatedcoldpainsensationinhumans |