Ethanol Disrupts Hormone-Induced Calcium Signaling in Liver.
Ethanol Disrupts Hormone-Induced Calcium Signaling in Liver.
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DOI：
10.1093/function/zqab002
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Bartlett PJ
中科院分区：
文献类型：
--
作者：
Gaspers LD;Thomas AP;Hoek JB;Bartlett PJ
受体偶联磷脂酶C （PLC）是乙醇作用的重要靶点。在离体灌注的大鼠肝脏中，需要浓度为100 mM的乙醇才能诱导胞质钙（Ca2+）的升高，这表明这些反应可能只发生在暴饮乙醇后。相反，药理学上可达到的乙醇浓度（≤30 mM）降低了激素刺激的细胞质和细胞核Ca2+振荡的频率和幅度，以及蛋白激酶C-β向膜的平行易位。乙醇还抑制间隙连接通信，导致肝小叶中协调和空间组织的细胞间Ca2+波的丧失。增加激素浓度克服了乙醇对Ca2+振荡频率和个体Ca2+瞬态振幅的影响；然而，完整肝脏中的Ca2+反应在细胞间水平上仍然紊乱，这表明间隙连接仍然受到抑制。用乙醇脱氢酶抑制剂预处理肝细胞抑制了乙醇对激素诱导的Ca2+增加的影响，而抑制醛脱氢酶则增强了乙醇的抑制作用，这表明乙醛是潜在的介质。急性乙醇中毒抑制了激素刺激下肌醇1,4,5-三磷酸（IP3）产生的上升速率和幅度，但对笼中IP3光解诱导的Ca2+峰值大小没有影响。这些结果表明，乙醇抑制PLC活性，但不影响IP3受体功能。我们提出，通过抑制激素刺激的PLC活性，乙醇干扰[IP3]的动态调制，这是产生大振幅Ca2+振荡所必需的。
Receptor-coupled phospholipase C (PLC) is an important target for the actions of ethanol. In the ex vivo perfused rat liver, concentrations of ethanol >100 mM were required to induce a rise in cytosolic calcium (Ca2+) suggesting that these responses may only occur after binge ethanol consumption. Conversely, pharmacologically achievable concentrations of ethanol (≤30 mM) decreased the frequency and magnitude of hormone-stimulated cytosolic and nuclear Ca2+ oscillations and the parallel translocation of protein kinase C-β to the membrane. Ethanol also inhibited gap junction communication resulting in the loss of coordinated and spatially organized intercellular Ca2+ waves in hepatic lobules. Increasing the hormone concentration overcame the effects of ethanol on the frequency of Ca2+ oscillations and amplitude of the individual Ca2+ transients; however, the Ca2+ responses in the intact liver remained disorganized at the intercellular level, suggesting that gap junctions were still inhibited. Pretreating hepatocytes with an alcohol dehydrogenase inhibitor suppressed the effects of ethanol on hormone-induced Ca2+ increases, whereas inhibiting aldehyde dehydrogenase potentiated the inhibitory actions of ethanol, suggesting that acetaldehyde is the underlying mediator. Acute ethanol intoxication inhibited the rate of rise and the magnitude of hormone-stimulated production of inositol 1,4,5-trisphosphate (IP3), but had no effect on the size of Ca2+ spikes induced by photolysis of caged IP3. These findings suggest that ethanol inhibits PLC activity, but does not affect IP3 receptor function. We propose that by suppressing hormone-stimulated PLC activity, ethanol interferes with the dynamic modulation of [IP3] that is required to generate large, amplitude Ca2+ oscillations.
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影响因子：
4.1
作者：
FEIERMAN, DE;CEDERBAUM, AI
通讯作者：
CEDERBAUM, AI
影响因子：
2.3
作者：
Dinis-Oliveira, Ricardo J.
通讯作者：
Dinis-Oliveira, Ricardo J.
影响因子：
3.9
作者：
CEDERBAUM, AI;RUBIN, E
通讯作者：
RUBIN, E
影响因子：
64.8
作者：
Fu, Suneng;Yang, Ling;Li, Ping;Hofmann, Oliver;Dicker, Lee;Hide, Winston;Lin, Xihong;Watkins, Steven M.;Ivanov, Alexander R.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
4
作者：
Bartlett, Paula J.;Gaspers, Lawrence D.;Thomas, Andrew P.
通讯作者：
Thomas, Andrew P.