@article{723612ced80b4b2191e319f26452ea3b,
title = "Importin a3 regulates chronic pain pathways in peripheral sensory neurons",
abstract = "How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin a3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin a3 knockout or sensory neuron-specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin a3-bound c-Fos and importin a3-deficient neurons were impaired in c-Fos nuclear import. Knockdown or dominant-negative inhibition of c-Fos or c-Jun in sensory neurons reduced neuropathic pain. In silico screens identified drugs that mimic importin a3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin a3 in peripheral neurons can promote analgesia.",
author = "Letizia Marvaldi and Nicolas Panayotis and Stefanie Alber and Dagan, \{Shachar Y.\} and Nataliya Okladnikov and Indrek Koppel and \{Di Pizio\}, Agostina and Didi-Andreas Song and Yarden Tzur and Marco Terenzio and Ida Rishal and Dalia Gordon and Franziska Rother and Enno Hartmann and Michael Bader and Mike Fainzilber",
note = "We thank V. Kiss, T. Shalit, M. Tsoory, and C. Pritz for excellent professional expertise; N. Korem and Y. Levi for technical assistance; and H. Song, C. Vinson, and V. Gradinaru for generous gifts of essential plasmids via Addgene. Funding: Supported by research grants from the European Research Council (Advanced grant Neurogrowth, Proof of Concept grant ChronicPain), the Irwin Green Alzheimer{\textquoteright}s Research Fund, the Simon Family Foundation, and Mr. and Mrs. Lawrence Feis. N.P., I.K., and M.T. were partly supported by Koshland senior postdoctoral fellowships, and N.P. was also supported by the Israeli Ministry of Immigrant Absorption. M.F. is supported by the Chaya Professorial Chair in Molecular Neuroscience at the Weizmann Institute of Science. Author contributions: Conceptualization: M.F. and L.M.; behavior and pain models: L.M., N.P., S.Y.D., N.O., and S.A.; immunohistochemistry, biochemistry, and data analyses: L.M., N.P., S.A., I.K., A.D.P., D.-A.S., Y.T., M.T., I.R., and D.G.; mouse models: F.R., E.H., and M.B.; writing and revision: M.F. and L.M., with input from all authors; supervision and funding: M.F. Competing interests: L.M. and M.F. have patent applications related to this work [Israeli application 268111, pending; Patent Cooperation Treaty (PCT) PCT/IL2020/050801]. Data and materials availability: All data are available in the main text or the supplementary materials. RNA sequencing datasets are available in the GEO database online (accession no. GSE137515). The importin α3 null mouse model is available upon request from M.B.{\textquoteright}s laboratory.",
year = "2020",
month = aug,
day = "14",
doi = "10.1126/science.aaz5875",
language = "الإنجليزيّة",
volume = "369",
pages = "842--846",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6505",
}