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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Functional characterization of two S-nitroso-L-cysteine transporters, which mediate movement of NO equivalents into vascular cells

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina

Submitted 12 July 2006 ; accepted in final form 6 November 2006

System L amino acid transporters have been shown to be responsible for cellular uptake of S-nitroso-L-cysteine (L-CSNO). In this study, we examined the characteristics of L-CSNO uptake in Xenopus laevis oocytes expressing system L transporters and found that uptake increased only when both 4F2 heavy chain (4F2HC) and either L-type amino acid transporter 1 (LAT1) or LAT2 light chain were coexpressed. The K_m for transport was 57 ± 8 µM for 4F2HC-LAT1 and 520 ± 52 µM for 4F2HC-LAT2. Vascular endothelial and smooth muscle cells were shown to express transcripts for 4F2HC and for both LAT1 and LAT2. Transport of L-CSNO into red blood cells, endothelial cells, and smooth muscle cells was inhibited by 2-aminobicyclo(2.2.1)heptane-2-carboxylic acid (BCH) and by large neutral amino acids demonstrating functional system L transporters in each cell type. Uptake of L-CSNO led to accumulation of cellular S-nitrosothiols and inhibition of both growth factor-induced ERK phosphorylation and TNF--mediated IB degradation. Similar effects were seen when cells were incubated simultaneously with S-nitrosoalbumin and L-cysteine but not with D-cysteine or with S-nitrosoalbumin alone. In each case, nitrosylation of proteins and cellular responses were blocked by BCH. Together, these data suggest that transmembrane movement of nitric oxide (NO) equivalents from the plasma albumin NO reservoir is mediated by cysteine, which serves as a carrier. The mechanism requires transnitrosylation from S-nitrosoalbumin to free cysteine and activity of system L transporters, thereby providing a unique pathway for cellular responses to S-nitrosoalbumin.

nitric oxide; nitrosothiols; system L transporter; endothelial cells; smooth muscle cells; red blood cells

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