Irbit mediates synergy between ca(2+) and cAMP signaling pathways during epithelial transport in mice.
Irbit mediates synergy between ca(2+) and cAMP signaling pathways during epithelial transport in mice.
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DOI：
10.1053/j.gastro.2013.03.047
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发表时间：
2013-07
期刊：
影响因子：
29.4
通讯作者：
Muallem S
中科院分区：
文献类型：
--
作者：
Park S;Shcheynikov N;Hong JH;Zheng C;Suh SH;Kawaai K;Ando H;Mizutani A;Abe T;Kiyonari H;Seki G;Yule D;Mikoshiba K;Muallem S
CAMP和Ca~(2+)信号通路协同调节多种生理功能。然而，人们对这些途径相互作用的机制知之甚少。我们研究了小鼠胰腺和唾液腺导管中这些信号通路之间的协同作用。我们创造了编码溶质载体家族26，成员6(SLC26a6−/−小鼠)和随InsP3释放的肌醇1，4，5-三磷酸(InsP3)受体结合蛋白的基因中断的小鼠(IRBIT−/−小鼠)。我们研究了封闭的胰管的液体分泌，以及在HeLa细胞和分离的小鼠胰腺和唾液腺的导管中SLc26a6和囊性纤维化跨膜电导调节因子(CFTR)的功能。通过测定细胞内pH测定SLC26a6活性，通过测定Cl-−电流测定CFtR活性。通过免疫沉淀分析确定蛋白质的相互作用。Irbit介导了钙离子和cAMP对CFTR和SLc26a6的协同激活作用。在静息细胞中，Irbit被内质网中的InsP3受体(IP3Rs)隔离。刺激Gs偶联受体导致IP3Rs的磷酸化，从而增加其对InsP3的亲和力，降低其对Irbit的亲和力。随后对Gq偶联受体的弱刺激导致低水平IP3的产生，导致Irbit从IP3Rs解离，并允许Irbit转位到质膜上的CFTR和SLc26a6。这些过程刺激上皮细胞分泌电解质和液体。这些通路在Irbit−/−或SLC26a6−/−小鼠的胰腺和唾液腺中没有观察到，也没有在表达突变形式的IP3R的唾液腺导管中观察到，这些突变形式的IP3Rs不能经历蛋白激酶A介导的磷酸化。IRBIT促进培养细胞以及小鼠胰腺和唾液管中钙离子和cAMP信号通路之间的协同作用。这一通路的缺陷可能与CF、胰腺炎或Sjögren综合征有关。
The cAMP and Ca2+ signaling pathways synergize to regulate many physiological functions. However, little is known about the mechanisms by which these pathways interact. We investigated the synergy between these signaling pathways in mouse pancreatic and salivary gland ducts. We created mice with disruptions in genes encoding the solute carrier family 26, member 6 (Slc26a6−/− mice) and inositol 1,4,5-triphosphate (InsP3) receptor-binding protein released with InsP3 (Irbit−/− mice). We investigated fluid secretion by sealed pancreatic ducts and the function of Slc26a6 and the cystic fibrosis transmembrane conductance regulator (CFTR) in HeLa cells and in ducts isolated from mouse pancreatic and salivary glands. Slc26a6 activity was assayed by measuring intracellular pH, and CFTR activity by measuring Cl− current. Protein interactions were determined by immunoprecipitation analyses. Irbit mediated the synergistic activation of CFTR and Slc26a6 by Ca2+ and cAMP. In resting cells, Irbit was sequestered by InsP3 receptors (IP3Rs) in the endoplasmic reticulum. Stimulation of Gs-coupled receptors led to phosphorylation of IP3Rs, which increased their affinity for InsP3 and reduced their affinity for Irbit. Subsequent weak stimulation of Gq-coupled receptors, which led to production of low levels of IP3, caused dissociation of Irbit from IP3Rs and allowed translocation of Irbit to CFTR and Slc26a6 in the plasma membrane. These processes stimulated epithelial secretion of electrolytes and fluid. These pathways were not observed in pancreatic and salivary glands from Irbit−/− or Slc26a6−/− mice, or in salivary gland ducts expressing mutant forms of IP3Rs that could not undergo protein kinase A-mediated phosphorylation. Irbit promotes synergy between the Ca2+ and cAMP signaling pathways in cultured cells and in pancreatic and salivary ducts from mice. Defects in this pathway could be involved in CF, pancreatitis, or Sjögren’s syndrome.
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DOI：
10.1085/jgp.200810097
发表时间：
2009-04
期刊：
The Journal of general physiology
影响因子：
--
作者：
Bertrand CA;Zhang R;Pilewski JM;Frizzell RA
通讯作者：
Frizzell RA
影响因子：
15.9
作者：
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通讯作者：
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DOI：
10.1016/j.bbrc.2012.06.127
发表时间：
2012-08-03
影响因子：
3.1
作者：
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通讯作者：
Ishikawa, Toru
影响因子：
5.5
作者：
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通讯作者：
Muallem, S
影响因子：
33.6
作者：
McCormick JA;Ellison DH
通讯作者：
Ellison DH