title: A role for Piezo2 in EPAC1-dependent mechanical allodynia.
abstract: 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.
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK. N.Eijkelkamp@umcutrecht.nl
authors.forename: N
authors.initials: N
authors.lastname: Eijkelkamp
authors.forename: J E
authors.initials: JE
authors.lastname: Linley
authors.forename: J M
authors.initials: JM
authors.lastname: Torres
authors.forename: L
authors.initials: L
authors.lastname: Bee
authors.forename: A H
authors.initials: AH
authors.lastname: Dickenson
authors.forename: M
authors.initials: M
authors.lastname: Gringhuis
authors.forename: M S
authors.initials: MS
authors.lastname: Minett
authors.forename: G S
authors.initials: GS
authors.lastname: Hong
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.forename: U
authors.initials: U
authors.lastname: Oh
authors.forename: Y
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: F J
authors.initials: FJ
authors.lastname: Zwartkuis
authors.forename: J J
authors.initials: JJ
authors.lastname: Cox
authors.forename: J N
authors.initials: JN
authors.lastname: Wood
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism / Q000502:physiology*; D006930:Hyperalgesia / Q000209:etiology*; D007473:Ion Channels / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009838:Oligodeoxyribonucleotides; D015398:Signal Transduction
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007473:Ion Channels; D009838:Oligodeoxyribonucleotides; C552921:Piezo2 protein, mouse