McGowan Tracy A, Madesh Muniswamy, Zhu Yanqing, Wang Lewei, Russo Mark, Deelman Leo, Henning Rob, Joseph Suresh, Hajnoczky Gyorgy, Sharma Kumar
Dorrance Hamilton Laboratory, Division of Nephrology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Am J Physiol Renal Physiol. 2002 May;282(5):F910-20. doi: 10.1152/ajprenal.00252.2001.
Ca(2+) influx has been postulated to modulate the signaling pathway of transforming growth factor-beta (TGF-beta); however, the underlying mechanism and functional significance of TGF-beta-induced stimulation of Ca(2+) influx are unclear. We show here that TGF-beta stimulates Ca(2+) influx in mesangial cells without Ca(2+) release. The influx of Ca(2+) is prevented by pharmacological inhibitors of inositol 1,4,5-trisphosphate receptors (IP(3)R) as well as specific antibodies to type III IP(3)R (IP(3)RIII) but not to type I IP(3)R (IP(3)RI). TGF-beta enhances plasma membrane localization of IP(3)RIII, whereas the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA) preferentially translocates to the nucleus. Untreated mesangial cells exhibit actin filamentous protrusions on the cell surface, and treatment with TGF-beta dramatically reduces this pattern. The alterations in the actin cytoskeleton by TGF-beta are dependent on TGF-beta-induced Ca(2+) influx. These studies identify a novel pathway by which TGF-beta regulates Ca(2+) influx and induces cytoskeletal alterations.
钙离子内流被认为可调节转化生长因子-β（TGF-β）的信号通路；然而，TGF-β诱导钙离子内流的潜在机制和功能意义尚不清楚。我们在此表明，TGF-β可刺激系膜细胞中的钙离子内流而不伴有钙离子释放。肌醇1,4,5-三磷酸受体（IP3R）的药理学抑制剂以及针对III型IP3R（IP3RIII）而非I型IP3R（IP3RI）的特异性抗体可阻止钙离子内流。TGF-β增强了IP3RIII在质膜的定位，而肌浆网-内质网钙离子ATP酶（SERCA）则优先转运至细胞核。未经处理的系膜细胞在细胞表面呈现肌动蛋白丝状突起，而用TGF-β处理可显著减少这种模式。TGF-β引起的肌动蛋白细胞骨架改变依赖于TGF-β诱导的钙离子内流。这些研究确定了一种新的途径，通过该途径TGF-β调节钙离子内流并诱导细胞骨架改变。
