Xu Hao, Zhao Ping, Zhang Wen-Jing, Qiu Jun-Ying, Tan Li, Liu Xiao-Cao, Wang Qian, Luo Xi, She Yu-Shan, Zang Dun-An, Liu Bei-Bei, Cao Lei, Zhao Xiao-Xue, Chen Yuan-Yuan, Li Meng-Yue, Shen Jinhua, Peng Yong-Bo, Xue Lu, Yu Meng-Fei, Chen Weiwei, Ma Li-Qun, Qin Gangjian, Liu Qing-Hua
Institute for Medical Biology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China.
Department of Biomedical Engineering, School of Medicine & School of Engineering, University of Alabama Birmingham, Birmingham, Alabama, USA.
Cell Physiol Biochem. 2018;47(4):1546-1555. doi: 10.1159/000490873. Epub 2018 Jun 21.
BACKGROUND/AIMS: Tetraethylammonium chloride (TEA) induces oscillatory contractions in mouse airway smooth muscle (ASM); however, the generation and maintenance of oscillatory contractions and their role in ASM are unclear.
In this study, oscillations of ASM contraction and intracellular Ca2+ were measured using force measuring and Ca2+ imaging technique, respectively. TEA, nifedipine, niflumic acid, acetylcholine chloride, lithium chloride, KB-R7943, ouabain, 2-Aminoethoxydiphenyl borate, thapsigargin, tetrodotoxin, and ryanodine were used to assess the mechanism of oscillatory contractions.
TEA induced depolarization, resulting in activation of L-type voltage-dependent Ca2+ channels (LVDCCs) and voltage-dependent Na+ (VNa) channels. The former mediated Ca2+ influx to trigger a contraction and the latter mediated Na+ entry to enhance the contraction via activating LVDCCs. Meanwhile, increased Ca2+-activated Cl- channels, inducing depolarization that resulted in contraction through LVDCCs. In addition, the contraction was enhanced by intracellular Ca2+ release from Ca2+ stores mediated by inositol (1,4,5)-trisphosphate receptors (IP3Rs). These pathways together produce the contractile phase of the oscillatory contractions. Furthermore, the increased Ca2+ activated the Na+-Ca2+ exchanger (NCX), which transferred Ca2+ out of and Na+ into the cells. The former induced relaxation and the latter activated Na+/K+-ATPase that induced hypopolarization to inactivate LVDCCs causing further relaxation. This can also explain the relaxant phase of the oscillatory contractions. Moreover, the depolarization induced by VNa channels and NCX might be greater than the hypopolarization caused by Na+/K+-ATPase alone, inducing LVDCC activation and resulting in further contraction.
These data indicate that the TEA-induced oscillatory contractions were cooperatively produced by LVDCCs, VNa channels, Ca2+-activated Cl- channels, NCX, Na+/K+ ATPase, IP3Rs-mediated Ca2+ release, and extracellular Ca2+.
背景/目的：氯化四乙铵（TEA）可诱导小鼠气道平滑肌（ASM）产生振荡性收缩；然而，振荡性收缩的产生和维持及其在ASM中的作用尚不清楚。
在本研究中，分别使用测力技术和Ca2+成像技术测量ASM收缩和细胞内Ca2+的振荡。使用TEA、硝苯地平、尼氟酸、氯化乙酰胆碱、氯化锂、KB-R7943、哇巴因、2-氨基乙氧基二苯硼酸、毒胡萝卜素、河豚毒素和ryanodine来评估振荡性收缩的机制。
TEA诱导去极化，导致L型电压依赖性Ca2+通道（LVDCCs）和电压依赖性Na+（VNa）通道激活。前者介导Ca2+内流以触发收缩，后者介导Na+内流以通过激活LVDCCs增强收缩。同时，Ca2+激活的Cl-通道增加，诱导去极化，通过LVDCCs导致收缩。此外，由肌醇（1,4,5）-三磷酸受体（IP3Rs）介导的Ca2+从Ca2+储存库中释放，增强了收缩。这些途径共同产生振荡性收缩的收缩期。此外，增加的Ca2+激活了Na+-Ca2+交换器（NCX），其将Ca2+转运出细胞并将Na+转运入细胞。前者诱导舒张，后者激活Na+/K+-ATP酶，诱导超极化使LVDCCs失活，导致进一步舒张。这也可以解释振荡性收缩的舒张期。此外，VNa通道和NCX诱导的去极化可能大于单独由Na+/K+-ATP酶引起的超极化，诱导LVDCCs激活并导致进一步收缩。
这些数据表明，TEA诱导的振荡性收缩是由LVDCCs、VNa通道、Ca2+激活的Cl-通道、NCX、Na+/K+ATP酶、IP3Rs介导的Ca2+释放和细胞外Ca2+协同产生的。
