Inflammatory Signals Enhance Piezo2-Mediated Mechanosensitive Currents

Abstract

Summary Heightened nociceptor function caused by inflammatory mediators such as bradykinin contributes to increased pain perception (hyperalgesia) to noxious mechanical and thermal stimuli. While sensitization of the heat transducer TRPV1 largely subserves thermal hyperalgesia, 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 bradykinin, an algogenic peptide that induces mechanical hyperalgesia within minutes. Piezo2 current amplitude is increased and inactivation slowed by bradykinin 2 receptor (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 bradykinin via PKA and PKC. Thus, piezo2 sensitization may contribute to PKA- and PKC-mediated mechanical hyperalgesia.

Novel methods of applying direct chemical and mechanical stimulation to the oral mucosa for traditional behavioral pain assays in conscious rats

“…The mechano-sensitive channels TRPA1, TRPV4 and Piezo2 have all been associated with mechanical hypersensitivity under conditions of inflammation and nerve injury (Alessandri-Haber et al, 2008;Bonet et al, 2013;Dubin et al, 2012). Therefore, these channels may be involved in the mechanical hypersensitivity induced by OUs.…”

Cell-Type-Specific Splicing of Piezo2 Regulates Mechanotransduction

“…However, our analysis has not been exhaustive as we did not examine all splice variants of Piezo2 and we did not investigate the potential interaction of Piezo2 with other membrane proteins. Other intracellular signaling pathways (Borbiro et al, 2015; Dubin et al, 2012) and protein interactions (Narayanan et al, 2016; Poole et al, 2014) have been shown to modulate Piezo2 function. More importantly, to fully appreciate the contribution of receptor diversification, it will be important to determine the in vivo consequences of Piezo2 splicing.…”

Piezo2 is the major transducer of mechanical forces for touch sensation in mice

“…Constitutive deletion of Piezo2 led to perinatal lethality; therefore, we used an inducible strategy to delete Piezo2 in adult mice 10 . The AvCreERT2 mouse line allowed for tamoxifen-induced activation of Cre recombinase under the Advillin promoter in sensory neurons and in epidermal Merkel Cells 11 .…”

“…We determined the sensitivity of cultured DRG neurons from Piezo2 CKO mice to mechanical indentation using a piezoelectrically-actuated blunt glass probe 10,13,14 . DRGs from Piezo2 CKO mice had dramatically fewer neurons with RA whole cell current responses compared to controls (Fig.…”