Benítez-Angeles Miguel, Romero Ana E López, Llorente Itzel, Hernández-Araiza Ileana, Vergara-Jaque Ariela, Real Fernando H, Gutiérrez Castañeda Óscar Eduardo, Arciniega Marcelino, Morales-Buenrostro Luis E, Torres-Quiroz Francisco, García-Villegas Refugio, Tovar-Y-Romo Luis B, Liedtke Wolfgang B, Islas León D, Rosenbaum Tamara
Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
Center for Bioinformatics, Simulation and Modelling (CBSM), Faculty of Engineering, Universidad de Talca, Talca, Chile.
J Physiol. 2023 May;601(9):1655-1673. doi: 10.1113/JP284262. Epub 2023 Jan 31.
The Transient Receptor Potential Vanilloid 4 (TRPV4) channel has been shown to function in many physiological and pathophysiological processes. Despite abundant information on its importance in physiology, very few endogenous agonists for this channel have been described, and very few underlying mechanisms for its activation have been clarified. TRPV4 is expressed by several types of cells, such as vascular endothelial, and skin and lung epithelial cells, where it plays pivotal roles in their function. In the present study, we show that TRPV4 is activated by lysophosphatidic acid (LPA) in both endogenous and heterologous expression systems, pinpointing this molecule as one of the few known endogenous agonists for TRPV4. Importantly, LPA is a bioactive glycerophospholipid, relevant in several physiological conditions, including inflammation and vascular function, where TRPV4 has also been found to be essential. Here we also provide mechanistic details of the activation of TRPV4 by LPA and another glycerophospholipid, lysophosphatidylcholine (LPC), and show that LPA directly interacts with both the N- and C-terminal regions of TRPV4 to activate this channel. Moreover, we show that LPC activates TRPV4 by producing an open state with a different single-channel conductance to that observed with LPA. Our data suggest that the activation of TRPV4 can be finely tuned in response to different endogenous lipids, highlighting this phenomenon as a regulator of cell and organismal physiology. KEY POINTS: The Transient Receptor Potential Vaniloid (TRPV) 4 ion channel is a widely distributed protein with important roles in normal and disease physiology for which few endogenous ligands are known. TRPV4 is activated by a bioactive lipid, lysophosphatidic acid (LPA) 18:1, in a dose-dependent manner, in both a primary and a heterologous expression system. Activation of TRPV4 by LPA18:1 requires residues in the N- and C-termini of the ion channel. Single-channel recordings show that TRPV4 is activated with a decreased current amplitude (conductance) in the presence of lysophosphatidylcholine (LPC) 18:1, while LPA18:1 and GSK101 activate the channel with a larger single-channel amplitude. Distinct single-channel amplitudes produced by LPA18:1 and LPC18:1 could differentially modulate the responses of the cells expressing TRPV4 under different physiological conditions.
瞬时受体电位香草酸受体4（TRPV4）通道已被证明在许多生理和病理生理过程中发挥作用。尽管关于其在生理学中的重要性已有大量信息，但针对该通道的内源性激动剂却鲜有报道，其激活的潜在机制也很少得到阐明。TRPV4在多种类型的细胞中表达，如血管内皮细胞、皮肤和肺上皮细胞，它在这些细胞的功能中发挥着关键作用。在本研究中，我们发现在内源性和异源表达系统中，溶血磷脂酸（LPA）均可激活TRPV4，确定该分子为TRPV4少数已知的内源性激动剂之一。重要的是，LPA是一种生物活性甘油磷脂，与多种生理状况相关，包括炎症和血管功能，而在这些过程中TRPV4也被发现至关重要。在此我们还提供了LPA和另一种甘油磷脂溶血磷脂酰胆碱（LPC）激活TRPV4的机制细节，并表明LPA直接与TRPV4的N端和C端区域相互作用以激活该通道。此外，我们发现LPC通过产生一种与LPA不同的单通道电导的开放状态来激活TRPV4。我们的数据表明，TRPV4的激活可根据不同的内源性脂质进行精细调节，突出了这一现象作为细胞和机体生理调节因子的作用。要点：瞬时受体电位香草酸受体（TRPV）4离子通道是一种广泛分布的蛋白质，在正常和疾病生理学中起重要作用，但其已知的内源性配体很少。在原代和异源表达系统中，生物活性脂质溶血磷脂酸（LPA）18:1以剂量依赖的方式激活TRPV4。LPA18:1激活TRPV4需要离子通道N端和C端的残基。单通道记录显示，在溶血磷脂酰胆碱（LPC）18:1存在的情况下，TRPV4被激活时电流幅度（电导）降低，而LPA18:1和GSK101以较大的单通道幅度激活该通道。LPA18:1和LPC18:1产生的不同单通道幅度可在不同生理条件下差异调节表达TRPV4的细胞的反应。
