Gabrielle Matthew, Yudin Yevgen, Wang Yujue, Su Xiaoyang, Rohacs Tibor
Department of Pharmacology, Physiology & Neuroscience, Rutgers University New Jersey Medical School, Newark NJ.
Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick NJ.
bioRxiv. 2024 Mar 2:2024.03.01.582964. doi: 10.1101/2024.03.01.582964.
Mechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively inhibit PIEZO2 over PIEZO1. The TMEM120A protein was shown to inhibit PIEZO2 while leaving PIEZO1 unaffected. Here we find that TMEM120A expression elevates cellular levels of phosphatidic acid and lysophosphatidic acid (LPA), aligning with its structural resemblance to lipid-modifying enzymes. Intracellular application of phosphatidic acid or LPA inhibited PIEZO2, but not PIEZO1 activity. Extended extracellular exposure to the non-hydrolyzable phosphatidic acid and LPA analogue carbocyclic phosphatidic acid (ccPA) also inhibited PIEZO2. Optogenetic activation of phospholipase D (PLD), a signaling enzyme that generates phosphatidic acid, inhibited PIEZO2, but not PIEZO1. Conversely, inhibiting PLD led to increased PIEZO2 activity and increased mechanical sensitivity in mice in behavioral experiments. These findings unveil lipid regulators that selectively target PIEZO2 over PIEZO1, and identify the PLD pathway as a regulator of PIEZO2 activity.
机械敏感的PIEZO2离子通道在触觉、本体感觉和炎性疼痛中发挥作用。目前，尚无能够选择性抑制PIEZO2而不影响PIEZO1的小分子抑制剂。研究表明，跨膜蛋白120A（TMEM120A）蛋白可抑制PIEZO2，而对PIEZO1无影响。在此，我们发现TMEM120A的表达会提高细胞内磷脂酸和溶血磷脂酸（LPA）的水平，这与其与脂质修饰酶的结构相似性相符。在细胞内施加磷脂酸或LPA可抑制PIEZO2，但不影响PIEZO1的活性。长时间细胞外暴露于不可水解的磷脂酸和LPA类似物环丙烷磷脂酸（ccPA）也可抑制PIEZO2。光遗传学激活磷脂酶D（PLD）（一种可生成磷脂酸的信号酶）可抑制PIEZO2，但不影响PIEZO1。相反，在行为实验中，抑制PLD会导致小鼠体内PIEZO2活性增加以及机械敏感性增强。这些发现揭示了选择性靶向PIEZO2而非PIEZO1的脂质调节因子，并确定PLD途径为PIEZO2活性的调节因子。
