Endogenous Piezo1 Can Confound Mechanically Activated Channel Identification and Characterization

@article{Dubin2017EndogenousPC,
  title={Endogenous Piezo1 Can Confound Mechanically Activated Channel Identification and Characterization},
  author={A. Dubin and Swetha E. Murthy and A. Lewis and Lucie Brosse and S. Cahalan and J. Grandl and B. Coste and A. Patapoutian},
  journal={Neuron},
  year={2017},
  volume={94},
  pages={266-270.e3}
}
A gold standard for characterizing mechanically activated (MA) currents is via heterologous expression of candidate channels in naive cells. Two recent studies described MA channels using this paradigm. TMEM150c was proposed to be a component of an MA channel partly based on a heterologous expression approach (Hong et al., 2016). In another study, Piezo1's N-terminal "propeller" domain was proposed to constitute an intrinsic mechanosensitive module based on expression of a chimera between a… Expand
Heterologous Expression of the Piezo1-ASIC1 Chimera Induces Mechanosensitive Currents with Properties Distinct from Piezo1
TLDR
The chimera results are discussed, potential interpretations are considered, and potential interpretations in light of the Matters Arising from Dubin et al. (2017), published concurrently in this issue of Neuron. Expand
Evidence for Mechanosensitive Channel Activity of Tentonin 3/TMEM150C
TLDR
Evidence is presented to support that TTN3 is a pore-forming unit, not an amplifying adaptor for Piezo1 activity, and evidence based on co-expression of TTN 3 and Peizo1 and mutant variants of the pore region of TTn3 is supported. Expand
TMEM120A/TACAN inhibits mechanically activated Piezo2 channels
TLDR
The data do not support TACAN being a mechanically activated ion channel, and identify it as a negative modulator of Piezo2 channel activity, and provide no support for its proposed role in nociceptive dorsal root ganglion neurons. Expand
Inactivation Kinetics and Mechanical Gating of Piezo1 Ion Channels Depend on Subdomains within the Cap
TLDR
It is shown by cysteine crosslinking that conformational flexibility of these subdomains is required for mechanical activation to occur and that electrostatic interactions functionally couple the cap to the extensive blades, which have been proposed to function as sensors of membrane curvature and tension. Expand
Patch-seq of mouse DRG neurons reveals candidate genes for specific mechanosensory functions
TLDR
Correlation of current signatures with single-cell transcriptomes provides a one-to-one correspondence between mechanoelectric properties and transcriptomically-defined neuronal populations, and gene expression differential comparison provides a set of candidate genes for mechanotransduction complexes. Expand
Inactivation of Mechanically Activated Piezo1 Ion Channels Is Determined by the C-Terminal Extracellular Domain and the Inner Pore Helix
TLDR
The globular C-terminal extracellular domain is identified as a structure that is sufficient to confer the time course of inactivation and a single positively charged lysine residue at the adjacent inner pore helix as being required for its voltage dependence. Expand
OSCA/TMEM63 are an Evolutionarily Conserved Family of Mechanically Activated Ion Channels
TLDR
The results suggest that OSCA/TMEM63 proteins are the largest family of MA ion channels identified, and are conserved across eukaryotes. Expand
TMEM150C/Tentonin3 Is a Regulator of Mechano-gated Ion Channels
TLDR
Functional interaction of TMEM150C with mechano-gated ion channels from different classes (Piezo2, Piezo1, and the potassium channel TREK-1) using two independent methods of mechanical stimulation is found to significantly prolongs the duration of the mechani-current produced by all three channels, decreases apparent activation threshold in Piezo 2, and induces persistent current inPiezo1. Expand
Functional analyses of heteromeric human PIEZO1 Channels
TLDR
High-resolution optical images of fluorescently-tagged channels support the interpretation that functional channels do not form from freely-diffusing, randomly-mixed monomers in-vitro, because coexpressed subunits segregate into discrete domains. Expand
Voltage gating of mechanosensitive PIEZO channels
TLDR
Electrophysiological measurements are presented that show that PIEZO channels are also modulated by voltage and can switch to a purely voltage gated mode, which is an evolutionary conserved property of this channel family. Expand
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References

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Heterologous Expression of the Piezo1-ASIC1 Chimera Induces Mechanosensitive Currents with Properties Distinct from Piezo1
TLDR
The chimera results are discussed, potential interpretations are considered, and potential interpretations in light of the Matters Arising from Dubin et al. (2017), published concurrently in this issue of Neuron. Expand
Evidence for Mechanosensitive Channel Activity of Tentonin 3/TMEM150C
TLDR
Evidence is presented to support that TTN3 is a pore-forming unit, not an amplifying adaptor for Piezo1 activity, and evidence based on co-expression of TTN 3 and Peizo1 and mutant variants of the pore region of TTn3 is supported. Expand
Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels
TLDR
Two genes that encode proteins, Piezo1 and Piezo2, are identified, which are required for mechanically stimulated cation conductance in these cells and in cultured dorsal root ganglion neurons, and it is proposed that Piezos are components of MA cation channels. Expand
The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.
TLDR
The ability of GsMTx4 to target the mechanosensitivity of Piezo1 supports the use of this channel in high-throughput screens for pharmacological agents and diagnostic assays. Expand
Piezo1 ion channel pore properties are dictated by C-terminal region
TLDR
Important structural motifs of this channel family are described and a glutamate residue within a conserved region adjacent to the last two putative TM domains of the protein is identified that affects unitary conductance and ion selectivity, and modulates pore block. Expand
Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes
TLDR
There are separate, but overlapping, mechanoelectrical transduction pathways in chondrocytes, and both TRPV4 and PIEZO1 channels contribute to currents activated by stimuli applied at cell-substrate contacts but only PIEzO1 mediates stretch-activated currents. Expand
Architecture of the mammalian mechanosensitive Piezo1 channel
TLDR
This cryo-electron microscopy structure of the full-length mouse Piezo1 (Piezo1) at a resolution of 4.8 Å suggests that piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore. Expand
Ion Permeation and Mechanotransduction Mechanisms of Mechanosensitive Piezo Channels
TLDR
This is the first report on the bona fide pore module and mechanotransduction components of Piezo channels, which define their ion-conducting properties and gating by mechanical stimuli, respectively. Expand
Tentonin 3/TMEM150c Confers Distinct Mechanosensitive Currents in Dorsal-Root Ganglion Neurons with Proprioceptive Function
TLDR
Identification of this gene advances the understanding of the various types of mechanosensations, including proprioception, and appears to be a component of a mechanosensitive channel with a slow inactivation rate and contributes to motor coordination. Expand
Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells
TLDR
It is proposed that the mechanically gated ion channel Piezo1 is an important determinant of mechanosensitive lineage choice in neural stem cells and may play similar roles in other multipotent stem cells. Expand
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