Molecular basis for calcium signaling in hepatic stellate cells.
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 Ca(2+) 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 Ca(2+) 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.
Kruglov
Emma A
EA
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St., LMP 1080, New Haven, CT 06520, USA.
Correa
Paulo R A V
PR
Arora
Gaurav
G
Yu
Jin
J
Nathanson
Michael H
MH
Dranoff
Jonathan A
JA
D021581:Active Transport, Cell Nucleus; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D037282:Calreticulin / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D048430:Cell Shape; D022081:Cell Surface Extensions / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013997:Time Factors
D037282:Calreticulin; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate