Mechanosensitive ion channels are force-transducing enzymes that couple mechanical stimuli to ion flux. Understanding the gating mechanism of mechanosensitive channels is challenging because the stimulus seen by the channel reflects forces shared between the membrane, cytoskeleton and extracellular matrix. Here we examine whether the mechanosensitive channel PIEZO1 is activated by force-transmission through the bilayer. To achieve this, we generate HEK293 cell membrane blebs largely free of cytoskeleton. Using the bacterial channel MscL, we calibrate the bilayer tension demonstrating that activation of MscL in blebs is identical to that in reconstituted bilayers. Utilizing a novel PIEZO1–GFP fusion, we then show PIEZO1 is activated by bilayer tension in bleb membranes, gating at lower pressures indicative of removal of the cortical cytoskeleton and the mechanoprotection it provides. Thus, PIEZO1 channels must sense force directly transmitted through the bilayer.

/pdf/removal-of-the-mechanoprotective-influence-of-the-3rtuslj6jr.pdf

Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 is gated by bilayer tension

Biophysical Principles of Ion-Channel-Mediated Mechanosensory Transduction.

The droplet on hydrogel bilayer (DHB) is a novel platform for investigating the function of ion channels. Advantages of this setup include tight control of all bilayer components, which is compelling for the investigation of mechanosensitive (MS) ion channels, since they are highly sensitive to their lipid environment. However, the activation of MS ion channels in planar supported lipid bilayers, such as the DHB, has not yet been established. Here we present the activation of the large conductance MS channel of E. coli, (MscL), in DHBs. By selectively stretching the droplet monolayer with nanolitre injections of buffer, we induced quantifiable DHB tension, which could be related to channel activity. The MscL activity response revealed that the droplet monolayer tension equilibrated over time, likely by insertion of lipid from solution. Our study thus establishes a method to controllably activate MS channels in DHBs and thereby advances studies of MS channels in this novel platform.

/pdf/activation-of-the-mechanosensitive-ion-channel-mscl-by-48u1mfehn2.pdf

Activation of the mechanosensitive ion channel MscL by mechanical stimulation of supported Droplet-Hydrogel bilayers.

Mechanosensory transduction is a fundamental process by which living cells convert environmental mechanical stimuli into relevant biological signals. This article highlights the major progress that has been achieved in studies of mechanosensitive (MS) channels, which play a prominent role in numerous mechanotransduction processes. We follow the history of MS channels from their conception to the determination of their molecular identity in both prokaryotic and eukaryotic cells. In the first section we focus on mechanotransduction in microbial and plant cells and describe briefly the structure, function, gating mechanism and pharmacology of MS channels in these cells. In the second part we focus on the diversity of MS channels linked to mechanosensory transduction in multicellular organisms. We discuss the molecular models that have been put forward to explain MS channel activation, including the contributions of the bilayer and structural scaffold proteins, and highlight the mysteries that are yet to be solved. As well as providing information on general mechanisms of ion channel mechanosensitivity we look at some special cases including what is known about the role of MS channels in auditory transduction and the cardiovascular system. We conclude by highlighting the role that MS channels play in the pathology of a wide array of both hereditary and multifactorial diseases and discuss why this structurally diverse group of channels encompasses a number of viable and attractive pharmaceutical targets.

Mechanosensory Transduction: Focus on Ion Channels

The bacterial mechanosensitive channel of small conductance (MscS) has been extensively studied to understand how mechanical forces are converted into the conformational changes that underlie mechanosensitive (MS) channel gating. We showed that lipid removal by β-cyclodextrin can mimic membrane tension. Here, we show that all cyclodextrins (CDs) can activate reconstituted Escherichia coli MscS, that MscS activation by CDs depends on CD-mediated lipid removal, and that the CD amount required to gate MscS scales with the channel's sensitivity to membrane tension. Importantly, cholesterol-loaded CDs do not activate MscS. CD-mediated lipid removal ultimately causes MscS desensitization, which we show is affected by the lipid environment. While many MS channels respond to membrane forces, generalized by the "force-from-lipids" principle, their different molecular architectures suggest that they use unique ways to convert mechanical forces into conformational changes. To test whether CDs can also be used to activate other MS channels, we chose to investigate the mechanosensitive channel of large conductance (MscL) and demonstrate that CDs can also activate this structurally unrelated channel. Since CDs can open the least tension-sensitive MS channel, MscL, they should be able to open any MS channel that responds to membrane tension. Thus, CDs emerge as a universal tool for the structural and functional characterization of unrelated MS channels.

Cyclodextrins increase membrane tension and are universal activators of mechanosensitive channels.

Mechanosensitive (MS) ion channels are molecular sensors that detect and transduce signals across prokaryotic and eukaryotic cell membranes arising from external mechanical stimuli or osmotic gradients. They play an integral role in mechanosensory responses including touch, hearing, and proprioception by opening or closing in order to facilitate or prevent the flow of ions and organic osmolytes. In this study we use a linear force model of MS channel gating to determine the gating membrane tension (γ) and the gating area change (ΔA) associated with the energetics of MscS channel gating in giant spheroplasts and azolectin liposomes. Analysis of Boltzmann distribution functions describing the dependence of MscS channel gating on membrane tension indicated that the gating area change (ΔA) was the same for MscS channels recorded in both preparations. The comparison of the membrane tension (γ) gating the channel, however, showed a significant difference between the MscS channel activities in these two preparations.

https://www.tandfonline.com/doi/pdf/10.4161/chan.28366

Energetics of gating MscS by membrane tension in azolectin liposomes and giant spheroplasts.

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Energetics of gating MscS by membrane tension in azolectin liposomes and giant spheroplasts.