Intercellular calcium waves integrate hormonal control of glucose output in the intact liver
Intercellular calcium waves integrate hormonal control of glucose output in the intact liver
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DOI：
10.1113/jp277650
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发表时间：
2019-06-01
影响因子：
5.5
通讯作者：
Thomas, Andrew P.
中科院分区：
文献类型：
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作者：
Gaspers, Lawrence D.;Pierobon, Nicola;Thomas, Andrew P.
交感神经流出和循环中的生糖激素都是通过增加细胞内钙来调节肝功能的，尽管这些钙信号是如何在组织水平上整合的目前尚不清楚。我们表明，刺激肝神经纤维或仅向肝脏灌流生理浓度的加压素将引起局部的胞浆钙振荡和肝脏葡萄糖生成的适度增加。这些刺激的组合协同作用，将局部和异步的钙反应转化为协调的细胞间钙波，扩散到整个肝小叶，并引起肝脏葡萄糖产量的协同增加。本研究的结果表明，一种激素的亚阈值水平可以通过肝小叶产生一种可兴奋的介质，从而允许钙信号的全球传播，以响应局部交感神经支配和多种激素对代谢调节的整合。这使得肝小叶能够作为功能单位做出反应，在激素的生理水平上产生完全强度的代谢输出。生糖激素，包括儿茶酚胺和加压素，在肝细胞中诱导频率调制的胞浆钙振荡，这些振荡通过完整肝脏的缝隙连接以细胞间钙波的形式传播。我们研究了协同的钙波作为一种整合多种内分泌和神经内分泌输入的机制来控制大鼠肝脏灌流中的葡萄糖产生。交感神经刺激可引起局限于门静脉周围区肝细胞的局部钙升高。在阈值以下血管加压素灌流期间，交感神经刺激将有限数量的肝细胞中的异步钙信号转换为协调的细胞间钙波，并在整个小叶中传播。在生理浓度的胰高血糖素和加压素之间也观察到了类似的协同作用，其中胰高血糖素也促进了肝细胞重新进入钙波。随着小叶内钙波的出现，肝脏葡萄糖产量显著增加。我们认为，依赖于肌醇1，4，5-三磷酸(IP3)的Ca~(2+)信号在肝小叶的功能合体中产生一个可兴奋的介质，协调和放大对多种激素输入的代谢反应。
Key pointsSympathetic outflow and circulating glucogenic hormones both regulate liver function by increasing cytosolic calcium, although how these calcium signals are integrated at the tissue level is currently unknown. We show that stimulation of hepatic nerve fibres or perfusing the liver with physiological concentrations of vasopressin only will evoke localized cytosolic calcium oscillations and modest increases in hepatic glucose production. The combination of these stimuli acted synergistically to convert localized and asynchronous calcium responses into co-ordinated intercellular calcium waves that spread throughout the liver lobule and elicited a synergistic increase in hepatic glucose production. The results obtained in the present study demonstrate that subthreshold levels of one hormone can create an excitable medium across the liver lobule, which allows global propagation of calcium signals in response to local sympathetic innervation and integration of metabolic regulation by multiple hormones. This enables the liver lobules to respond as functional units to produce full-strength metabolic output at physiological levels of hormone. Glucogenic hormones, including catecholamines and vasopressin, induce frequency-modulated cytosolic Ca2+ oscillations in hepatocytes, and these propagate as intercellular Ca2+ waves via gap junctions in the intact liver. We investigated the role of co-ordinated Ca2+ waves as a mechanism for integrating multiple endocrine and neuroendocrine inputs to control hepatic glucose production in perfused rat liver. Sympathetic nerve stimulation elicited localized Ca2+ increases that were restricted to hepatocytes in the periportal zone. During perfusion with subthreshold vasopressin, sympathetic stimulation converted asynchronous Ca2+ signals in a limited number of hepatocytes into co-ordinated intercellular Ca2+ waves that propagated across entire lobules. A similar synergism was observed between physiological concentrations of glucagon and vasopressin, where glucagon also facilitated the recruitment of hepatocytes into a Ca2+ wave. Hepatic glucose production was significantly higher with intralobular Ca2+ waves. We propose that inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signalling gives rise to an excitable medium across the functional syncytium of the hepatic lobule, co-ordinating and amplifying the metabolic responses to multiple hormonal inputs.