Extracellular Calcium Sensing Receptor Stimulation in Human Colonic Epithelial Cells Induces Intracellular Calcium Oscillations and Proliferation Inhibition

被引:60
作者
Rey, Osvaldo [1 ,2 ]
Young, Steven H. [1 ,2 ]
Jacamo, Rodrigo [3 ]
Moyer, Mary P. [4 ]
Rozengurt, Enrique [1 ,2 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med,Mol Biol Inst, Dept Med,Div Digest Dis,CURE Digest Dis Res Ctr, Unit Signal Transduct & Gastrointestinal Canc, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Sect Mol Hematol & Therapy, Houston, TX 77030 USA
[4] INCELL Corp, San Antonio, TX USA
关键词
PROTEIN-KINASE-C; FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; NEONATAL SEVERE HYPERPARATHYROIDISM; COLORECTAL-CANCER; CA2+-SENSING RECEPTOR; VITAMIN-D; CA2+ OSCILLATIONS; DIETARY CALCIUM; GASTROINTESTINAL-TRACT; PROSPECTIVE COHORT;
D O I
10.1002/jcp.22198
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The extracellular Ca(2+)-sensing receptor (CaR) is increasingly implicated in the regulation of multiple cellular functions in the gastrointestinal tract, including secretion, proliferation and differentiation of intestinal epithelial cells. However, the signaling mechanisms involved remain poorly defined. Here we examined signaling pathways activated by the CaR, including Ca(2+) oscillations, in individual human colon epithelial cells. Single cell imaging of colon-derived cells expressing the CaR, including SW-480, HT-29, and NCM-460 cells, shows that stimulation of this receptor by addition of aromatic amino acids or by an elevation of the extracellular Ca(2+) concentration promoted striking intracellular Ca(2+) oscillations. The intracellular calcium oscillations in response to extracellular Ca(2+) were of sinusoidal pattern and mediated by the phospholipase C/diacylglycerol/inositol 1,4,5-trisphosphate pathway as revealed by a biosensor that detects the accumulation of diacylglrerol in the plasma membrane. The intracellular calcium oscillations in response to aromatic amino acids were of transient type, that is, Ca(2+) spikes that returned to baseline levels, and required an intact actin cytoskeleton, a functional Rho, Filamin A and the ion channel TRPC1. Further analysis showed that re-expression and stimulation of the CaR in human epithelial cells derived from normal colon and from colorectal adenocarcinoma inhibits their proliferation. This inhibition was associated with the activation of the signaling pathway that mediates the generation of sinusoidal, but not transient, intracellular Ca(2+) oscillations. Thus, these results indicate that the CaR can function in two signaling modes in human colonic epithelial cells offering a potential link between gastrointestinal responses and food/nutrients uptake and metabolism. J. Cell. Physiol. 225: 73-83, 2010. (C) 2010 Wiley-Liss, Inc.
引用
收藏
页码:73 / 83
页数:11
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