Cells adeptly navigate complex environments, perceiving and responding to diverse stimuli, with mechanical signals playing a critical role in processes such as touch and hearing. Mechanosensitive ion channels, a specialized class of proteins, including the OSCA/TMEM63 family, are key players in detecting mechanical signals. When activated by force in the surrounding membrane, these channels transition from a closed to an open conformation, creating a pathway for ions and converting mechanical stimuli into electrochemical signals for downstream signal transduction.

Despite their importance, the precise structural basis of how these channels are activated by mechanical force remains largely unknown. A major obstacle is the difficulty in applying a defined mechanical force during structural data collection, making it an important yet challenging area of investigation.

In view of this, Prof. ZHANG Yixiao's team from the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences aimed to capture the open structure of OSCA/TMEM63 channels using different and complementary strategies. Their initial approaches involved nanodiscs, small lipid bilayer patches surrounded by a scaffolding protein, to mimic increased membrane tension.

By reducing the number of lipids per nanodisc, the researchers induced lipid expansion in nanodiscs, thereby increasing tension around the embedded OSCA/TMEM63 proteins. While these experiments provided clues to the gating process of these channels, it was structures of OSCA channels reconstituted into small liposomes - spherical lipid vesicles - that induced significant local tension around the channel that gave them the clearest picture of the open OSCA channel.

In parallel, they used computational and electrophysiological approaches to guide and interpret these structural studies. Through these combined structural, functional and computational studies, they revealed how the OSCA/TMEM63 channels respond to mechanical force, with lipids playing a distinct and critical role in the conformational transitions.

The most exciting observation was that, unlike typical ion channels where the pore is completely surrounded by protein, the pore in their activated OSCA channel had a lateral opening to the membrane - meaning that the pathway for ion permeation was lined by lipids.

Their structural and simulation data showed that headgroups of lipids organize along the pore, acting as a lipid wall to guide ion passage. This configuration is best supported by their functional data showing that the lipid headgroup charge can modulate the ion selectivity of the channel.

Thus, their work not only provides a global view of the gating cycle of OSCA/TMEM63 channels, but also unambiguously identifies a "proteo-lipidic" pore for ion permeation, first proposed by Criss Hartzell in TMEM16 proteins.  

Given that the wall lipids line the pore, and considering the ability of the related TMEM16 proteins to scramble lipids, one might immediately ask whether OSCA/TMEM63 channels can function as mechanosensitive lipid scramblers, and what the physiological role of such scramblase activity might be.

In future studies, Prof. ZHANG Yixiao's team is excited to explore the potential mechanosensitive lipid scramblase properties of OSCA/TMEM63 channels and apply their force mimicking methods to other mechanosensitive channels.  

The proteo-lipidic pore of OSCA1.2 (Image by ZHANG Yixiao)