A role for Piezo2 in EPAC1-dependent mechanical allodynia Eijkelkamp, N. Torres de Pinedo, Jesús Manuel Protein-Kinase-C Mechanosensitive Ion Channels Sensory neurons Intrathecal morphine Inflammatory pain Neurophatic pain Cell adhesion Epac proteins Rat Sensitization N.E. and J.W. designed and supervised experiments. N.E. performed most of the in vivo and in vitro experiments. J.L. performed experiments to characterize hPiezo2. G.H and G.L. supervised by U.O., and J.T. and J.C. cloned hPiezo. L.B. performed the in vivo electrophysiology under the supervision of A.D. M.G. helped with the overexpression studies.M.M. performed surgery. Y.I. provided the Epac1 / mice. F.Z. provided the Epac constructs. N.E. and J.W. wrote manuscript with contributions of all authors. N.E., J.L. and L.B. contributed to data analysis and all authors contributed to the discussions 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. 2020-11-04T11:27:27Z 2020-11-04T11:27:27Z 2013-04-09 info:eu-repo/semantics/article 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] http://hdl.handle.net/10481/64046 10.1038/ncomms2673 eng http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess Atribución-NoComercial-SinDerivadas 3.0 España Nature Publishing Group