Importin α3 regulates chronic pain pathways in peripheral sensory neurons

Science. 2020 Aug 14;369(6505):842-846. doi: 10.1126/science.aaz5875. | PubMed

Letizia Marvaldi¹, Nicolas Panayotis¹, Stefanie Alber¹, Shachar Y Dagan¹, Nataliya Okladnikov¹, Indrek Koppel¹, Agostina Di Pizio¹, Didi-Andreas Song¹, Yarden Tzur¹, Marco Terenzio^1,2, Ida Rishal¹, Dalia Gordon¹, Franziska Rother^3,4, Enno Hartmann⁴, Michael Bader^3,4,5, Mike Fainzilber⁶

1. Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
2. Molecular Neuroscience Unit, Okinawa Institute of Science and Technology, Kunigami-gun, Okinawa 904-0412, Japan.
3. Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
4. Center for Structural and Cellular Biology in Medicine, Institute of Biology, University of Lübeck, 23538 Lübeck, Germany.
5. Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
6. Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. mike.fainzilber@weizmann.ac.il.

Abstract

How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin α3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin α3 knockout or sensory neuron-specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin α3-bound c-Fos and importin α3-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 α3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin α3 in peripheral neurons can promote analgesia.

Presented By Letizia Marvaldi | ORCID iD