Wijerathne Tharaka D, Bhatt Aashish, Jiang Wenjuan, Luo Yun L, Lacroix Jerome J
Department of Biomedical Sciences, Western University of Health Sciences, Pomona, California.
Department of Biotechnology and Pharmaceutical Sciences, Western University of Health Sciences, Pomona, California.
Biophys J. 2024 Nov 14. doi: 10.1016/j.bpj.2024.11.010.
Under physiological conditions, mammalian PIEZO channels (PIEZO1 and PIEZO2) elicit transient currents mostly carried by monovalent and divalent cations. PIEZO1 is also known to permeate chloride ions, with a Cl/Na permeability ratio of about 0.2. Yet, little is known about how anions permeate PIEZO channels. Here, by separately measuring sodium and chloride currents using nonpermanent counterions, we show that both PIEZO1 and PIEZO2 rectify chloride currents outwardly, favoring entry of chloride ions at voltages above their reversal potential, whereas little to no rectification was observed for sodium currents. Interestingly, chloride currents elicited by 9K, an anion-selective PIEZO1 mutant harboring multiple positive residues along intracellular pore fenestrations, also rectify but in the inward direction. Molecular dynamics simulations reveal that the inward rectification of chloride currents in 9K correlates with the presence of a large positive electrostatic potential at intracellular pore fenestrations, suggesting that rectification can be tuned by the electrostatic polarity of the pore. These results demonstrate that the pore of mammalian PIEZO channels inherently rectifies chloride currents.
在生理条件下，哺乳动物的PIEZO通道（PIEZO1和PIEZO2）引发的瞬态电流主要由单价和二价阳离子携带。已知PIEZO1也能通透氯离子，其Cl/Na通透率约为0.2。然而，关于阴离子如何通透PIEZO通道却知之甚少。在这里，通过使用非永久性抗衡离子分别测量钠电流和氯电流，我们发现PIEZO1和PIEZO2都能使氯电流向外整流，在高于其反转电位的电压下有利于氯离子进入，而钠电流几乎没有或没有观察到整流现象。有趣的是，由9K（一种阴离子选择性PIEZO1突变体，在细胞内孔窗处有多个正残基）引发的氯电流也会整流，但方向向内。分子动力学模拟表明，9K中氯电流的内向整流与细胞内孔窗处存在大的正静电势有关，这表明整流可以通过孔的静电极性来调节。这些结果表明，哺乳动物PIEZO通道的孔本身就能使氯电流整流。
