Sam George Shefin, Ricci Anthony J
Department of Otolaryngology-Head and Neck Surgery, Stanford University, Palo Alto, 94304, USA.
Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, 94304, USA.
Adv Sci (Weinh). 2025 Sep 4:e08268. doi: 10.1002/advs.202508268.
The plasma membrane is actively regulated by lipid transporters that create electrochemical gradients between leaflets, and passively by scramblases that dissipate these gradients. Membrane properties such as lipid packing are critical for the proper function of transmembrane proteins, particularly mechanosensitive ion channels. Mechanosensation is a key component of many sensory processes including balance, and hearing. Inner ear hair cells convert mechanical deflection of their hair bundles into electrical signals by gating mechanoelectrical transduction (MET) channels. Transmembrane channel-like proteins (TMCs) are an essential component of the hair cell MET complex, and part of a superfamily of molecules whose members are ion channels and/or lipid scramblases. TMCs are implicated as scramblases in hair cells, however no direct evidence separates scramblase activity from channel properties, nor is there clarity around how MET activity impacts the stereocilia environment. Here, using a novel viscosity sensor boron-dipyrromethene (BODIPY) 1c, this work probes stereocilia membrane viscosity and its relationship with TMC expression and MET current. Using developmental, genetic, electrophysiological and pharmacological tools, this work demonstrates that the MET complex directly regulates the stereocilia membrane viscosity. This work shows that phosphatidylserine externalization does not completely describe, nor solely represent TMC scramblase activity. Lipid flippase/floppase activity along with an MET independent scramblase are implicated in lipid remodeling. Together these data identify a dynamic regulation of stereocilia membrane hypothesized to modulate mechanotransduction channel properties.
质膜受到脂质转运蛋白的主动调节，这些转运蛋白在细胞膜内外小叶之间形成电化学梯度，同时也受到磷脂翻转酶的被动调节，后者会消除这些梯度。诸如脂质堆积等膜特性对于跨膜蛋白的正常功能至关重要，尤其是对机械敏感离子通道而言。机械感觉是包括平衡和听力在内的许多感觉过程的关键组成部分。内耳毛细胞通过开启机械电转导（MET）通道，将其毛束的机械偏转转化为电信号。跨膜通道样蛋白（TMC）是毛细胞MET复合体的重要组成部分，并且是一个分子超家族的一部分，其成员包括离子通道和/或脂质翻转酶。TMC被认为是毛细胞中的翻转酶，然而，尚无直接证据将翻转酶活性与通道特性区分开来，而且MET活性如何影响静纤毛环境也尚不清楚。在这里，这项研究使用一种新型粘度传感器硼二吡咯亚甲基（BODIPY）1c，探究静纤毛膜粘度及其与TMC表达和MET电流的关系。利用发育、遗传、电生理和药理学工具，这项研究表明MET复合体直接调节静纤毛膜粘度。这项研究表明，磷脂酰丝氨酸外化并不能完全描述，也不能单独代表TMC翻转酶活性。脂质翻转酶/转位酶活性以及一种不依赖MET的翻转酶与脂质重塑有关。这些数据共同确定了静纤毛膜的动态调节，推测其可调节机械转导通道特性。
