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LIVER AND BILIARY TRACT

Molecular basis for calcium signaling in hepatic stellate cells

¹Section of Digestive Diseases, Department of Internal Medicine, and ²Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut

Submitted 28 August 2006 ; accepted in final form 18 December 2006

Progressive liver fibrosis (with the resultant cirrhosis) is the primary cause of chronic liver failure. Hepatic stellate cells (HSCs) are critically important mediators of liver fibrosis. In the healthy liver, HSCs are quiescent lipid-storing cells limited to the perisinusoidal endothelium. However, in the injured liver, HSCs undergo myofibroblastic transdifferentiation (activation), which is a critical step in the development of organ fibrosis. HSCs express P2Y receptors linking extracellular ATP to inositol (1,4,5)-trisphosphate-mediated cytosolic Ca²⁺ signals. Here, we report that HSCs express only the type I inositol (1,4,5)-trisphosphate receptor and that the receptor shifts into the nucleus and cell extensions upon activation. These cell extensions, furthermore, express sufficient machinery to enable local application of ATP to evoke highly localized Ca²⁺ signals that induce localized contractions. These autonomous units of subcellular signaling and response reveal a new level of subcellular organization, which, in turn, establishes a novel paradigm for the local control of fibrogenesis in the liver.

nucleoplasmic reticulum; liver fibrosis; contractility; P2Y receptor

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