A role for Piezo2 in EPAC1-dependent mechanical allodynia
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Nature Publishing Group
Protein-Kinase-CMechanosensitive Ion ChannelsSensory neuronsIntrathecal morphineInflammatory painNeurophatic painCell adhesionEpac proteinsRatSensitization
Eijkelkamp, N., Linley, J. E., Torres, J. M., Bee, L., Dickenson, A. H., Gringhuis, M., ... & Ishikawa, Y. (2013). A role for Piezo2 in EPAC1-dependent mechanical allodynia. Nature communications, 4(1), 1-13. [DOI: 10.1038/ncomms2673]
SponsorshipNetherlands Organization for Scientific Research (NWO); Jose Castillejo fellowship JC2010-0196; Spanish Government; Medical Research Council UK (MRC); WCU at SNU R31-2008-000-10103-0; EU IMI Europain grant; BBSRC LOLA grant; Wellcome Trust; Versus Arthritis 20200; Biotechnology and Biological Sciences Research Council (BBSRC) BB/F000227/1; Medical Research Council UK (MRC) G0901905 G9717869 G1100340
Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-induced allodynia is reduced in Epac1 / mice. The Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents in sensory neurons. Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton. In vivo, 8-pCPT induces long-lasting allodynia that is prevented by the knockdown of Epac1 and attenuated by mouse Piezo2 knockdown. Piezo2 knockdown also enhanced thresholds for light touch. Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres. These data indicate that the Epac1–Piezo2 axis has a role in the development of mechanical allodynia during neuropathic pain.