Stress differentially induces cationic amino acid transporter gene expression.

The amino acid l-arginine plays a central role in several adaptive metabolic pathways and we postulate that regulated L-arginine transport contributes to important physiological responses. The majority of L-arginine flux is mediated by transport system y+ that is encoded by at least three genes, Cat1, Cat2 and Cat3. Cat2 encodes two distinct protein isoforms (CAT2/CAT2a) that differ by 10-fold in their apparent substrate affinity. Cat2 transcription is controlled by four widely spaced promoters. The expression of CAT2/2a transcripts was tested in skeletal muscle and macrophages following specific stresses or activators. Unexpectedly, CAT2a transcripts accumulated in skeletal muscle in response to surgical trauma (hepatectomy and splenectomy) as well as food deprivation, although neither high affinity CAT2 nor CAT1 were detectably altered. Activated macrophages decreased CAT1 levels, but accumulated CAT2 and iNOS mRNA and protein with parallel kinetics suggesting that CAT2 mediated L-arginine transport might regulate the L-arginine:nitric oxide pathway. In macrophages, liver and skeletal muscle, the most distal CAT2 promoter was predominant. No change in promoter usage was apparent under any stress conditions tested nor was alternate splicing of the CAT2 transcript dictated by promoter usage. The differential regulation of the Cat genes indicates their encoded transporter proteins meet different requirements for cationic amino acids in the intact animal.