Aims

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. Its molecular mechanism is still unclear. Endoplasmic reticulum (ER) stress has been highlighted in PD. Transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium cation channel. A defined role for TRPV4 in PD has not been reported. The purpose of the present research was to investigate the molecular mechanisms by which TRPV4 regulates ER stress induced by the 1-methyl-4-phenylpyridinium ion (MPP⁺) in PC12 cells.

Main methods

PC12 cells were pretreated with the TRPV4-specific antagonist HC067047 or transfected with TRPV4 siRNA followed by treatment with MPP⁺. Cell viability was measured by the CCK-8 Assay. The expression of TRPV4, sarco/endoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2), glucose-regulated protein 78 (GRP78), glucose-regulated protein 94 (GRP94), C/EBP homologous protein (CHOP), procaspase-12, and tyrosine hydroxylase (TH) was detected by western blot and RT-PCR.

Key findings

The expression of TRPV4 was upregulated, while cell viability was decreased by MPP⁺, which was reversed by HC067047. The ER stress common molecular signature SERCA2 was depressed by MPP⁺. Moreover, MPP⁺ induced upregulation of GRP78, GRP94, CHOP, and decrease in procaspase-12 and TH. HC067047 and TRPV4 siRNA reversed MPP⁺-induced ER stress and restored TH production.

Significance

TRPV4 functions upstream of ER stress induced by MPP⁺ and holds promise as a prospective pharmacotherapy target for PD.

中文翻译：

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TRPV4导致内质网应激：与MPP +诱导的帕金森氏病细胞模型中的细胞凋亡有关。

目的

帕金森氏病（PD）是一种多因素神经退行性疾病。其分子机制仍不清楚。内质网（ER）应激已在PD中得到强调。瞬时受体电位香草酸4（TRPV4）是一种非选择性钙阳离子通道。尚未报道TRPV4在PD中的明确作用。本研究的目的是研究TRPV4调节PC12细胞中1-甲基-4-苯基吡啶鎓离子（MPP ⁺）诱导的ER应激的分子机制。

主要方法

PC12细胞用TRPV4特异性拮抗剂HC067047预处理，或用TRPV4 siRNA转染，然后用MPP ⁺处理。通过CCK-8测定法测量细胞活力。TRPV4，肌浆网/内质网Ca ²⁺ -ATPase 2（SERCA2），葡萄糖调节蛋白78（GRP78），葡萄糖调节蛋白94（GRP94），C / EBP同源蛋白（CHOP），procaspase-12， Western blot和RT-PCR检测酪氨酸羟化酶（TH）。

主要发现

TRPV4的表达上调，而MPP ⁺降低了细胞活力，而HC067047则逆转了。MPP ⁺抑制ER应力共同分子标记SERCA2 。此外，MPP ⁺诱导GRP78，GRP94，CHOP的上调，并降低procaspase-12和TH。HC067047和TRPV4 siRNA逆转了MPP ⁺诱导的ER应激并恢复了TH产生。

意义

TRPV4在MPP ⁺诱导的ER应激的上游起作用，并有望成为PD的预期药物治疗靶标。