The hepatic stellate cell (HSC) is recognized as one of the key mediators in the progression of hepatic fibrosis.1-3 In the normal healthy liver, HSCs function to regulate sinusoidal blood flow and the traffic of macromolecules across the space of Disse and also act as a store for vitamin A. In response to hepatic injury, HSCs undergo a gross morphological change in terms of both function and phenotype in a process termed "activation", transforming to that of myofibroblast-like cell.1-3 The myofibroblast-like activated HSC (aHSC) is characterized by the expression of smooth muscle ␣-actin (␣-SMA), enhanced collagen production, expression of the tissue inhibitor of metalloproteinases-1, and the loss of vitamin A stores. Additionally, on activation, the normally quiescent HSC enters the cell cycle and, in response to both autocrine and paracrine stimulators, proliferates to produce a population of profibrogenic cells in the injured liver. Because the aHSC phenotype is relatively resistant to apoptosis due in part to the antiapoptotic effects of tissue inhibitor of metalloproteinases-1 and their high basal nuclear factor-B activity, 4,5 there is a propensity in the chronically injured liver for aHSCs to persist and perpetuate. This leads to the excess deposition of cross-linked collagen resulting in both qualitative and quantitative modification of the hepatic extracellular matrix (ECM).6 If this process of ECM remodeling continues, then the liver becomes fibrotic, and cirrhosis eventually develops, accompanied by life threatening disturbance of normal liver physiology. There is currently much interest in improving our understanding of how HSC proliferation and apoptosis are regulated because in vivo experimental manipulation of these processes is known to attenuate the fibrogenic process. 5,[7][8][9] In particular, there is a drive to discover novel surface receptors on aHSCs that are able to attenuate proliferation and/or apoptosis in response to specific ligands.

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The aim of the study was to investigate the role of glutamate residue 113 in transmembrane domain 2 of the human noradrenaline transporter in determining cell surface expression and functional activity. This residue is absolutely conserved in all members of the Na + -and Cl --dependent transporter family.Mutations to alanine (hE113A), aspartate (hE113D) and glutamine (hE113Q) were achieved by site-directed mutagenesis and the mutants were expressed in transfected COS-7 or HEK-293 cells. Cell surface expression of hE113A and hE113D, but not hE113Q, was markedly reduced compared with wild type, and functional noradrenaline uptake was detected only for the hE113Q mutant. The pharmacological properties of the hE113Q mutant showed very little change compared with wild type, except for a decrease in V max values for noradrenaline and dopamine uptake of 2-3-fold. However, the hE113D mutant showed very marked changes in its properties, compared with wild type, with 82-260-fold decreases in the affinities of the substrates, noradrenaline, dopamine and MPP + , and increased Na + affinity for stimulation of nisoxetine binding. The results of the study show that the size and not the charge of the 113 glutamate residue of the noradrenaline transporter seems to be the most critical factor for maintenance of transporter function and surface expression.

The interactions of -conopeptide

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