Proteomics

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Multisite phosphorylation by protein kinase A mediates modality-specific modulation of PIEZO2


ABSTRACT: Protein kinase A is a downstream effector of many inflammatory mediators that induce pain hypersensitivity by increasing the mechanosensitivity of nociceptive sensory afferent. Here we examine the molecular mechanism underlying protein kinase-Adependent modulation of the mechanically-activated ion channel PIEZO2, which confers mechanosensitivity to many nociceptors. Using phosphorylation site prediction algorithms, we identified multiple putative and highly conserved PKA phosphorylation sites located on intracellular intrinsically disordered regions of PIEZO2. Site-directed mutagenesis and patch-clamp recordings showed that substitution of one or multiple putative PKA sites within a single intracellular domains does not alter PKA-induced PIEZO2 sensitization, whereas mutation of a combination of nine putative sites located on four different intracellular regions completely abolishes PKA-dependent PIEZO2 modulation, suggesting that the effect requires multisite phosphorylation. By demonstrating that PIEZO1 is not modulated by PKA, our data also reveals a previously unrecognized functional difference between PIEZO1 and PIEZO2. Moreover, by demonstrating that PKA only modulates PIEZO2 currents evoked by focal mechanical indentation of the cell, but not currents evoked by pressure-induced membrane stretch, we provide evidence suggesting that PIEZO2 is a polymodal mechanosensor that engages different protein domains for detecting different types of mechanical stimuli.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Thomas Mair  

LAB HEAD: Stefan G Lechner

PROVIDER: PXD041372 | Pride | 2023-07-20

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
230303_PIEZO2_Pure_Kit.msf Msf
230303_PIEZO_Kit_8B1.raw Raw
230303_PIEZO_Kit_GFKT.raw Raw
230303_PIEZO_Pure_8B1_20230313193220.raw Raw
230303_PIEZO_Pure_GFKT_20230313174158.raw Raw
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Publications

PKA mediates modality-specific modulation of the mechanically gated ion channel PIEZO2.

Schaefer Irina I   Verkest Clement C   Vespermann Lucas L   Mair Thomas T   Voß Hannah H   Zeitzschel Nadja N   Lechner Stefan G SG  

The Journal of biological chemistry 20230504 6


PKA is a downstream effector of many inflammatory mediators that induce pain hypersensitivity by increasing the mechanosensitivity of nociceptive sensory afferent. Here, we examine the molecular mechanism underlying PKA-dependent modulation of the mechanically activated ion channel PIEZO2, which confers mechanosensitivity to many nociceptors. Using phosphorylation site prediction algorithms, we identified multiple putative and highly conserved PKA phosphorylation sites located on intracellular i  ...[more]

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