The sensation of mechanical stimuli is initiated by elastic gating springs that pull open mechanosensory transduction channels. Searches for gating springs have focused on force-conveying protein tethers such as the amino-terminal ankyrin tether of the Drosophila mechanosensory transduction channel NOMPC. Here, by combining protein domain duplications with mechanical measurements, electrophysiology, molecular dynamics simulations and modeling, we identify the NOMPC gating-spring as the short linker between the ankyrin tether and the channel gate. This linker acts as a Hookean hinge that is ten times more elastic than the tether, with the linker hinge dictating channel gating and the intrinsic stiffness of the gating spring. Our study shows how mechanosensation is initiated molecularly; disentangles gating springs and tethers, and respective paradigms of channel gating; and puts forward gating springs as core ion channel constituents that enable efficient gating by diverse stimuli and in a wide variety of channels.
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http://dx.doi.org/10.1038/s41593-024-01849-3 | DOI Listing |
Nat Neurosci
January 2025
Department of Cellular Neurobiology, University of Göttingen, Göttingen, Germany.
The sensation of mechanical stimuli is initiated by elastic gating springs that pull open mechanosensory transduction channels. Searches for gating springs have focused on force-conveying protein tethers such as the amino-terminal ankyrin tether of the Drosophila mechanosensory transduction channel NOMPC. Here, by combining protein domain duplications with mechanical measurements, electrophysiology, molecular dynamics simulations and modeling, we identify the NOMPC gating-spring as the short linker between the ankyrin tether and the channel gate.
View Article and Find Full Text PDFJ Allergy Clin Immunol
December 2024
University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA. Electronic address:
Over the past two decades, guidelines for the on-demand treatment of hereditary angioedema (HAE) attacks have undergone significant evolution. Early treatment guidelines, such as the Canadian 2003 International Consensus Algorithm, often gated on-demand treatment by attack location and/or severity. Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor [C1INH], icatibant, ecallantide [US only], recombinant C1INH), which were approved in the US and EU between 2008-2014, were designed accordingly.
View Article and Find Full Text PDFNeuron
December 2024
State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center of Biological Structure, Tsinghua University, Beijing 100084, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China. Electronic address:
PIEZO1 is a mechanically activated cation channel that undergoes force-induced activation and inactivation. However, its distinct structural states remain undefined. Here, we employed an open-prone PIEZO1-S2472E mutant to capture an intermediate open structure.
View Article and Find Full Text PDFJ Clin Transl Sci
October 2024
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Efficient evidence generation to assess the clinical and economic impact of medical therapies is critical amid rising healthcare costs and aging populations. However, drug development and clinical trials remain far too expensive and inefficient for all stakeholders. On October 25-26, 2023, the Duke Clinical Research Institute brought together leaders from academia, industry, government agencies, patient advocacy, and nonprofit organizations to explore how different entities and influencers in drug development and healthcare can realign incentive structures to efficiently accelerate evidence generation that addresses the highest public health needs.
View Article and Find Full Text PDFSci Rep
December 2024
Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, 94304, CA, USA.
In our ears, outer-hair-cell bundles (OHBs) convert sound-induced forces into receptor currents that drive cochlear amplification, the process responsible for the micropascal-scale threshold and million-fold dynamic range of hearing. OHBs rely on gating springs to open mechanoelectrical-transduction (MET) ion channels, through which the receptor current flows. OHBs have larger gating-spring stiffnesses than other types of hair bundles, but we have a poor understanding of how gating-spring stiffness contributes to OHB mechanics and receptor-current regulation.
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