Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2-mediated mechanotransduction in peripheral sensory neurons
- Max Planck Institute for Experimental Medicine, Germany
- University of Göttingen, Germany
- Heidelberg University, Germany
Abstract
Piezo2 ion channels are critical determinants of the sense of light touch in vertebrates. Yet, their regulation is only incompletely understood. We recently identified myotubularin related protein-2 (Mtmr2), a phosphoinositide (PI) phosphatase, in the native Piezo2 interactome of murine dorsal root ganglia (DRG). Here, we demonstrate that Mtmr2 attenuates Piezo2-mediated rapidly adapting mechanically activated (RA-MA) currents. Interestingly, heterologous Piezo1 and other known MA current subtypes in DRG appeared largely unaffected by Mtmr2. Experiments with catalytically inactive Mtmr2, pharmacological blockers of PI(3,5)P2 synthesis, and osmotic stress suggest that Mtmr2-dependent Piezo2 inhibition involves depletion of PI(3,5)P2. Further, we identified a PI(3,5)P2 binding region in Piezo2, but not Piezo1, that confers sensitivity to Mtmr2 as indicated by functional analysis of a domain-swapped Piezo2 mutant. Altogether, our results propose local PI(3,5)P2 modulation via Mtmr2 in the vicinity of Piezo2 as a novel mechanism to dynamically control Piezo2-dependent mechanotransduction in peripheral sensory neurons.
Data availability
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Native Piezo2 Interactomics Identifies Pericentrin as a Novel Regulator of Piezo2 in Somatosensory NeuronsAvailable at DOI: 10.1021/acs.jproteome.6b00235.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (SCHM 2533/2-1)
- Manuela Schmidt
Max-Planck-Gesellschaft (Open-access funding)
- Meike Hütte
- David Gomez-Varela
- Manuela Schmidt
Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und Molekulare Biowissenschaften (PhD fellowship)
- Pratibha Narayanan
- Meike Hütte
Deutsche Forschungsgemeinschaft (CRC889 Project A9)
- Manuela Schmidt
Deutsche Forschungsgemeinschaft (GO 2481/2-1)
- David Gomez-Varela
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments involving primary tissue isolated from mice were carried out in strict accordance with the recommendations of the institutional animal care and use committee (IACUC) of the Max Planck Institute of Experimental Medicine, Goettingen.
Copyright
© 2018, Narayanan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2-mediated mechanotransduction in peripheral sensory neurons
eLife 7:e32346.
https://doi.org/10.7554/eLife.32346
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