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Abstract：
Airway smooth muscle (ASM) contraction is determined by the increase in intracellular Ca2+ concentration ([Ca2+]i) caused by its release from the sarcoplasmic reticulum (SR) or by extracellular Ca2+ influx. Major channels involved in Ca2+ influx in ASM cells are L-type voltage-dependent Ca2+ channels (L-VDCCs) and nonselective cation channels (NSCCs). Transient receptor potential vanilloid 4 (TRPV4) is an NSCC recently studied in ASM. Mechanical stimuli, such as contraction, can activate TRPV4. We investigated the possible activation of TRPV4 by histamine (His)- or carbachol (CCh)-induced contraction in guinea pig ASM. In single myocytes, the TRPV4 agonist (GSK101) evoked an increase in [Ca2+]i, characterized by a slow onset and a plateau phase. The TRPV4 antagonist (GSK219) decreased channel activity by 94%, whereas the Ca2+-free medium abolished the Ca2+ response induced by GSK101. Moreover, GSK101 caused Na+ influx in tracheal myocytes. GSK219 reduced the Ca2+ peak and the Ca2+ plateau triggered by His or CCh. TRPV4 blockade shifted the concentration-response curve relating to His and CCh to the right in tracheal rings and reduced the maximal contraction. Finally, the activation of TRPV4 in single myocytes increased the Ca2+ refilling of the SR. We conclude that contraction of ASM cells after stimulation with His or CCh promotes TRPV4 activation, the subsequent influx of Ca2+ and Na+, and the opening of L-VDCCs. The entry of Ca2+ into ASM cells via TRPV4 and L-VDCCs contributes to optimal smooth muscle contraction.
摘要：
气道平滑肌（ASM）收缩是由其从肌浆网（SR）释放或由细胞外Ca2流入引起的细胞内Ca2浓度（[Ca2]i）的增加决定的。参与ASM细胞中Ca2流入的主要通道是L型电压依赖性Ca2通道（L-VDCC）和非选择性阳离子通道（NSCC）。瞬时受体电位香草酸4（TRPV4）是最近在ASM中研究的NSCC。机械刺激,如收缩，可以激活TRPV4。我们研究了豚鼠ASM中组胺（His）或卡巴胆碱（CCh）引起的收缩对TRPV4的可能激活。在单个肌细胞中，TRPV4激动剂（GSK101）引起[Ca2+]i增加，其特征是缓慢发作和平台期。TRPV4拮抗剂（GSK219）使通道活性降低了94％，而无Ca2+培养基消除了GSK101诱导的Ca2+反应。此外，GSK101引起气管肌细胞中的Na+内流。GSK219降低了由His或CCh触发的Ca2峰和Ca2平台。TRPV4阻滞使气管环中与His和CCh相关的浓度-反应曲线向右移动，并减少了最大收缩。最后,单个肌细胞中TRPV4的激活增加了SR的Ca2再填充。我们得出结论，用His或CCh刺激后ASM细胞的收缩促进TRPV4的激活，随后流入的Ca2+和Na+，以及L-VDCC的打开。Ca2+通过TRPV4和L-VDCC进入ASM细胞有助于最佳的平滑肌收缩。
