title: Inflammatory signals enhance piezo2-mediated mechanosensitive currents.
abstract: Heightened nociceptor function caused by inflammatory mediators such as bradykinin (BK) contributes to increased pain sensitivity (hyperalgesia) to noxious mechanical and thermal stimuli. Although it is known that sensitization of the heat transducer TRPV1 largely subserves thermal hyperalgesia, the cellular mechanisms underlying mechanical hyperalgesia have been elusive. The role of the mechanically activated (MA) channel piezo2 (known as FAM38B) present in mammalian sensory neurons is unknown. We test the hypothesis that piezo2 activity is enhanced by BK, an algogenic peptide that induces mechanical hyperalgesia within minutes. Piezo2 current amplitude is increased and inactivation is slowed by bradykinin receptor beta 2 (BDKRB2) activation in heterologous expression systems. Protein kinase A (PKA) and protein kinase C (PKC) agonists enhance piezo2 activity. BDKRB2-mediated effects are abolished by PKA and PKC inhibitors. Finally, piezo2-dependent MA currents in a class of native sensory neurons are enhanced 8-fold by BK via PKA and PKC. Thus, piezo2 sensitization may contribute to PKA- and PKC-mediated mechanical hyperalgesia.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. adubin@scripps.edu
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Dubin
authors.forename: Manuela
authors.initials: M
authors.lastname: Schmidt
authors.forename: Jayanti
authors.initials: J
authors.lastname: Mathur
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Petrus
authors.forename: Bailong
authors.initials: B
authors.lastname: Xiao
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coste
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008465:Mechanoreceptors / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; C577825:FAM3B protein, human; D009363:Neoplasm Proteins; D043782:Receptor, Bradykinin B2; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D001920:Bradykinin