miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus
Qingjian Hana, Di Liua, Marino Convertinob, Zilong Wanga, Changyu Jianga, Yong Ho Kima, Xin Luoa, Xin Zhanga, Andrea G. Nackleya, Nikolay V. Dokholyanb, Ru‐Rong Jia c d✉
- aCenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA
- bDepartment of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
- cDepartment of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: ru-rong.ji@duke.edu
- dDepartment of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA
- ✉Corresponding author
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Abstract
SUMMARY Increasing evidence suggests that extracellular miRNAs may serve as biomarkers of diseases, but the physiological relevance of extracellular miRNA is unclear. We find that intradermal cheek injection of miR-711 induces TRPA1-depedent itch (scratching) without pain (wiping) in naïve mice. Extracellular perfusion of miR-711 induces TRPA1 currents in both Trpa1-expressing heterologous cells and native sensory neurons through the core sequence GGGACCC. Computer simulations reveal that the core sequence binds several residues at the extracellular S5-S6 loop of TRPA1, which are critical for TRPA1 activation by miR-711 but not allyl isothiocyanate. Intradermal inoculation of human Myla cells induces lymphoma and chronic itch in immune- deficient mice, associated with increased serum levels of miR-711, secreted from cancer cells. Lymphoma-induced chronic itch is suppressed by miR-711 inhibitor and a blocking peptide that disrupts the miR-711/TRPA1 interaction. Our findings demonstrated an unconventional physiological role of extracellular naked miRNAs as itch mediators and ion channel modulators.
TL;DRThe findings demonstrated an unconventional physiological role of extracellular naked miRNAs as itch mediators and ion channel modulators. (Semantic Scholar)