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Inflammatory Signals Enhance Piezo2-Mediated Mechanosensitive Currents
- Source :
- 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⟩
- Publisher :
- The Authors. Published by Elsevier Inc.
-
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 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....7e33710a983e3a1a56fc547095a90408
- Full Text :
- https://doi.org/10.1016/j.celrep.2012.07.014