KCNQ1 is an essential mediator of the sex-dependent perception of moderate cold temperatures

Aytug K Kiper ¹, Sven Wegner ¹, Aklesso Kadala ², Susanne Rinné ¹, Sven Schütte ¹, Zoltán Winter ², Mirjam A R Bertoune ³, Filip Touska ², Veronika Matschke ⁴, Eva Wrobel ⁵, Anne-Kathrin Streit ¹, Florian Lang ⁶, Constanze Schmidt ⁷, Eric Schulze-Bahr ⁸, Martin K-H Schäfer ³, Jakob Voelkl ⁹, Guiscard Seebohm ^4 8, Katharina Zimmermann ^# 2, Niels Decher ^# 1

Affiliations expand

• PMID: 38857404
• PMCID: PMC11194602
• DOI: 10.1073/pnas.2322475121

Abstract

Low temperatures and cooling agents like menthol induce cold sensation by activating the peripheral cold receptors TRPM8 and TRPA1, cation channels belonging to the TRP channel family, while the reduction of potassium currents provides an additional and/or synergistic mechanism of cold sensation. Despite extensive studies over the past decades to identify the molecular receptors that mediate thermosensation, cold sensation is still not fully understood and many cold-sensitive peripheral neurons do not express the well-established cold sensor TRPM8. We found that the voltage-gated potassium channel KCNQ1 (Kv7.1), which is defective in cardiac LQT1 syndrome, is, in addition to its known function in the heart, a highly relevant and sex-specific sensor of moderately cold temperatures. We found that KCNQ1 is expressed in skin and dorsal root ganglion neurons, is sensitive to menthol and cooling agents, and is highly sensitive to moderately cold temperatures, in a temperature range at which TRPM8 is not thermosensitive. C-fiber recordings from KCNQ1^-/- mice displayed altered action potential firing properties. Strikingly, only male KCNQ1^-/- mice showed substantial deficits in cold avoidance at moderately cold temperatures, with a strength of the phenotype similar to that observed in TRPM8^-/- animals. While sex-dependent differences in thermal sensitivity have been well documented in humans and mice, KCNQ1 is the first gene reported to play a role in sex-specific temperature sensation. Moreover, we propose that KCNQ1, together with TRPM8, is a key instrumentalist that orchestrates the range and intensity of cold sensation.

Allergy. 2024 Mar 13. doi: 10.1111/all.16086. 

RNA-sequencing of paired tape-strips and skin biopsies in atopic dermatitis reveals key differences

Blaine Fritz ¹, Anne-Sofie Halling ², Isabel Díaz-Pinés Cort ¹, Maria Oberländer Christensen ², Amalie Thorsti Møller Rønnstad ², Caroline Meyer Olesen ², Mette Hjorslev Knudgaard ³, Claus Zachariae ^3 4, Steffen Heegaard ⁴, Jacob P Thyssen ^2 4, Thomas Bjarnsholt ^1 5

• PMID: 38477552
• DOI: 10.1111/all.16086

Abstract

Background: Skin tape-strips and biopsies are widely used methods for investigating the skin in atopic dermatitis (AD). Biopsies are more commonly used but can cause scarring and pain, whereas tape-strips are noninvasive but sample less tissue. The study evaluated the performance of skin tape-strips and biopsies for studying AD.

Methods: Whole-transcriptome RNA-sequencing was performed on paired tape-strips and biopsies collected from lesional and non-lesional skin from AD patients (n = 7) and non-AD controls (n = 5). RNA yield, mapping efficiency, and differentially expressed genes (DEGs) for the two methods (tape-strip/biopsy) and presence of AD (AD/non-AD) were compared.

Results: Tape-strips demonstrated a lower RNA yield (22 vs. 4596 ng) and mapping efficiency to known genes (28% vs. 93%) than biopsies. Gene-expression profiles of paired tape-strips and biopsies demonstrated a medium correlation (R² = 0.431). Tape-strips and biopsies demonstrated systematic differences in measured expression levels of 6483 genes across both AD and non-AD samples. Tape-strips preferentially detected many itch (CCL3/CCL4/OSM) and immune-response (CXCL8/IL4/IL5/IL22) genes as well as markers of epidermal dendritic cells (CD1a/CD207), while certain cytokines (IL18/IL37), skin-barrier genes (KRT2/FLG2), and dermal fibroblasts markers (COL1A/COL3A) were preferentially detected by biopsies. Tape-strips identified more DEGs between AD and non-AD (3157 DEGs) then biopsies (44 DEGs). Tape-strips also detected higher levels of bacterial mRNA than biopsies.

Conclusions: This study concludes that tape-strips and biopsies each demonstrate respective advantages for measuring gene-expression changes in AD. Thus, the specific skin layers and genes of interest should be considered before selecting either method.

Keywords: RNA sequencing; atopic dermatitis; biopsies; inflammation; tape-strips.

© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.