Expression and function of TRP channels in liver cells.

The liver plays a central role in whole body homeostasis by mediating the metabolism of carbohydrates, fats, proteins, drugs and xenobiotic compounds, and bile acid and protein secretion. Hepatocytes together with endothelial cells, Kupffer cells, smooth muscle cells, stellate and oval cells comprise the functioning liver. Many members of the TRP family of proteins are expressed in hepatocytes.

Ca(2+) -permeable channels in the hepatocyte plasma membrane and their roles in hepatocyte physiology.

Hepatocytes are highly differentiated and spatially polarised cells which conduct a wide range of functions, including intermediary metabolism, protein synthesis and secretion, and the synthesis, transport and secretion of bile acids. Changes in the concentrations of Ca(2+) in the cytoplasmic space, endoplasmic reticulum (ER), mitochondria, and other intracellular organelles make an essential contribution to the regulation of these hepatocyte functions. While not yet fully understood, the spatial and temporal parameters of the cytoplasmic Ca(2+) signals and the entry of Ca(2+) through Ca(2+)-permeable channels in the plasma membrane are critical to the regulation by Ca(2+) of hepatocyte function.

Hepatic ischemia-reperfusion injury: roles of Ca2+ and other intracellular mediators of impaired bile flow and hepatocyte damage.

Liver resection and liver transplantation have been successful in the treatment of liver tumors and end-stage liver disease. This success has led to an expansion in the pool of patients potentially treatable by liver surgery and, in the case of transplantation, to a shortage of liver donors. At present, there are significant numbers of potential candidates for liver resection and liver donation who have fatty livers, are aged, or have livers damaged by chemotherapy.

TRPM8 in prostate cancer cells: a potential diagnostic and prognostic marker with a secretory function?

During the past 5 years it has emerged that the transient receptor potential (TRP) family of Ca(2+)-and Na(+)-permeable channels plays a diverse and important role in cell biology and in pathology. One member of this family, TRPM8, is highly expressed in prostate cancer cells but the physiological and pathological functions of TRPM8 in these cells are not known. Here we address these questions, and the issue of whether or not TRPM8 is an effective diagnostic and prognostic marker in prostate cancer.

Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells.

The Ca(2+)-permeable channel TRPM8 is thought to play an important role in the pathophysiology of prostate cancer. We have investigated the intracellular location of TRPM8 and its role as a Ca(2+)-permeable channel in an androgen-responsive and an androgen-insensitive prostate cancer cell line. We report evidence from immunofluorescence experiments that in the androgen-responsive LNCaP cell line, the TRPM8 protein is expressed in the endoplasmic reticulum and plasma membrane, acts as a Ca(2+)-permeable channel (assessed using Fura-2 to measure increases in the cytoplasmic Ca(2+) concentration) in each of these membranes, and is regulated by androgen.

Induction of cholestasis in the perfused rat liver by 2-aminoethyl diphenylborate, an inhibitor of the hepatocyte plasma membrane Ca2+ channels.

Background And Aims: An increase in the cytoplasmic free Ca2+ concentration in hepatocytes as a result of the release of Ca2+ from intracellular stores and Ca2+ inflow from the extracellular space is a necessary part of the mechanism by which bile acids are moved along the bile cannaliculus by contraction of the cannaliculus. 2-Aminoethyl diphenylborate (2-APB) is a recently discovered inhibitor of store-operated plasma membrane Ca2+ channels in hepatocytes. The aim of the present study was to test the ability of 2-APB to inhibit bile flow.

Fast Ca(2+)-dependent inactivation of the store-operated Ca2+ current (ISOC) in liver cells: a role for calmodulin.

Store-operated Ca2+ channels (SOCs) provide a major pathway for Ca2+ entry in non-excitable cells. SOCs in immortalized liver cells are highly selective for Ca2+ over other cations and are similar to well-studied Ca2+ release activated Ca2+ (CRAC) channels in haematopoietic cell lines. In the present work, employing H4IIE liver cells, we investigated fast inactivation of SOC current (ISOC), which occurs at membrane potentials below -60 mV.

Evidence that Ca2+-release-activated Ca2+ channels in rat hepatocytes are required for the maintenance of hormone-induced Ca2+ oscillations.

Store-operated Ca(2+) channels in liver cells have been shown previously to exhibit a high selectivity for Ca(2+) and to have properties indistinguishable from those of Ca(2+)-release-activated Ca(2+) (CRAC) channels in mast cells and lymphocytes [Rychkov, Brereton, Harland and Barritt (2001) Hepatology 33, 938-947]. The role of CRAC channels in the maintenance of hormone-induced oscillations in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](cyt)) in isolated rat hepatocytes was investigated using several inhibitors of CRAC channels. 2-Aminoethyl diphenylborate (2-APB; 75 microM), Gd(3+) (1 microM) and 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride (SK&F 96365; 50 microM) each inhibited vasopressin- and adrenaline (epinephrine)-induced Ca(2+) oscillations (measured using fura-2).