Inflammatory Signals Enhance Piezo2-Mediated Mechanosensitive Currents
| Autor: | Bailong Xiao, Bertrand Coste, Manuela Schmidt, Adrienne E. Dubin, Ardem Patapoutian, Matthew J. Petrus, Jayanti Mathur |
|---|---|
| Přispěvatelé: | Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Předmět: |
medicine.medical_specialty
Thapsigargin Receptor Bradykinin B2 [SDV]Life Sciences [q-bio] Biophysics TRPV1 TRPV Cation Channels Bradykinin General Biochemistry Genetics and Molecular Biology Article Membrane Potentials 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Humans Bradykinin receptor Enzyme Inhibitors Protein kinase A lcsh:QH301-705.5 ComputingMilieux_MISCELLANEOUS Protein Kinase C Protein kinase C 030304 developmental biology Bradykinin receptor B2 Inflammation 0303 health sciences Nociceptors Cyclic AMP-Dependent Protein Kinases Cell biology Neoplasm Proteins Rats Endocrinology HEK293 Cells lcsh:Biology (General) chemistry Hyperalgesia Nociceptor Cytokines Mechanosensitive channels medicine.symptom Mechanoreceptors 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports Cell Reports, Elsevier Inc, 2012, 2 (3), pp.511-517. ⟨10.1016/j.celrep.2012.07.014⟩ Cell Reports, Vol 2, Iss 3, Pp 511-517 (2012) Cell Reports, 2012, 2 (3), pp.511-517. ⟨10.1016/j.celrep.2012.07.014⟩ |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2012.07.014 |
| Popis: | 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 present in mammalian sensory neurons is unknown. We tested the hypothesis that piezo2 activity is enhanced by BK, an algogenic peptide that induces mechanical hyperalgesia within minutes. We elicited piezo2-mediated currents by poking transiently transfected HEK293T cells with a blunt glass probe. Piezo2 current amplitude increases and inactivation is slowed by activation of exogenous bradykinin receptor B2. The area under the curve was enhanced 6.5-fold by BK compared with vehicle. Inclusion of GDPbetaS in the pipette occluded both effects on amplitude and inactivation. The protein kinase A (PKA) and protein kinase C (PKC) agonists 8-BrcAMP and PMA, respectively, enhanced piezo2 activity. No enhancement of piezo2-mediated currents was observed during exposure to the PLC activator m-3M3FBS (25 microM), suggesting phosphatidylinositol-PLC pathways do not increase piezo2 activity; inhibition of store release by thapsigargin had no effect on BK-induced changes. The PKA inhibitor H-89 and PKC inhibitor BIM I applied together effectively abrogated the BK-induced changes. Finally, piezo2-dependent MA currents in a class of native sensory neurons are enhanced 8-fold by BK via a PKA and PKC dependent mechanism, similarly to that observed in HEK cells. Thus, piezo2 sensitization may contribute to PKA- and PKC-mediated mechanical hyperalgesia. The mechanism described here differs from another model of mechanical hyperalgesia (epinephrine-induced PKCe-mediated) in which the downstream effector of cAMP is EPAC rather than PKA, since the BK effects observed here require PKA activity, and neither PI-PLC nor phospholipase D appears to be involved. |
| Databáze: | OpenAIRE |
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