The role of Drosophila Piezo in mechanical nociception

Abstract

Transduction of mechanical stimuli by receptor neurons is essential for senses such as hearing, touch, and pain1–4. Ion channels play a role in neuronal mechanotransduction in invertebrates1; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, NOMPC, a TRP ion channel, acts as a mechanotransducer in Drosophila melanogaster5 and Caenorhabditis elegans6,7; however, it has no orthologues in mammals. DEG/ENaC family members are mechanotransducers in C. elegans8 and potentially in D. melanogaster9; however, a direct role of its mammalian homologues in sensing mechanical force is not shown. Recently, Piezo1 and Piezo2 were identified as components of mechanically activated (MA) channels in mammals10. Piezos represent an evolutionary conserved family of transmembrane proteins. It is unknown whether Piezos function in mechanical sensing in vivo, and if they do, which mechanosensory modalities they mediate. Here, we study the physiological role of the single Piezo member in D. melanogaster (dpiezo). dpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts [Coste et al., accompanying paper11]. Behavioral responses to noxious mechanical stimuli were severely reduced in dpiezo knockout larvae, while responses to another noxious stimulus or touch were not affected. Knocking down dpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of dpiezo in these same neurons rescued the phenotype of the constitutive dpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a dpiezo dependent, mechanically-activated current. Finally, we found that dpiezo and ppk function in parallel pathways in ppk-positive cells, and that mechanical nociception is abolished in the absence of both channels. These data demonstrate physiological relevance of Piezo family in mechanotransduction in vivo, supporting a role of Piezo proteins in mechanosensory nociception.

Piezo Proteins: Regulators of Mechanosensation and Other Cellular Processes

“…Knockdown of Piezo2 in whisker hair follicles pre-sensitized with capsaicin injection suppresses pain responses (64). In flies, full genomic or sensory neuron-specific ablation of the Piezo orthologue leads to a severe and specific defect in noxious mechanotransduction (67). Together, these data strongly link Piezo2 function with noxious mechanosensation at physiological level.…”

Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells

“…Of these, Piezo1 was expressed at much greater levels than the other channels. The Piezo channels recently were shown to mediate physiologically relevant mechanically activated and nonspecific cationic currents in mammals (30)(31)(32)(33)(34). Like the endogenous hNSPC SAC, Piezo1 is inactivated by persisting mechanical stimuli (31) and is sensitive to GsMTx-4 (35).…”

Pickpocket1 Is an Ionotropic Molecular Sensory Transducer

“…Nociception Assay-Nociceptive responses to noxious mechanical stimuli were assayed using a standard protocol (2,18). In brief, third instar larvae in the wandering stage were exposed to a transient, noxious mechanical stimulus applied to the third, fourth, or fifth segment of the abdominal region with a 46-mN Von Frey filament.…”

“…Although there are many examples of ion channel receptors that can respond to sensory stimuli (1)(2)(3)(4)(5)(6)(7)(8), there are few examples where activation of these channels can drive neuronal activity.…”