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Pertussis toxin activates L-arginine uptake in pulmonary endothelial cells through downregulation of PKC- activity

Department of Medicine, University of Florida College of Medicine, Gainesville 32610; and Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida 32608

Submitted 17 July 2003 ; accepted in final form 12 December 2003

Pertussis toxin (PTX) induces activation of L-arginine transport in pulmonary artery endothelial cells (PAEC). The effects of PTX on L-arginine transport appeared after 6 h of treatment and reached maximal values after treatment for 12 h. PTX-induced changes in L-arginine transport were not accompanied by changes in expression of cationic amino acid transporter (CAT)-1 protein, the main L-arginine transporter in PAEC. Unlike holotoxin, the -oligomer-binding subunit of PTX did not affect L-arginine transport in PAEC, suggesting that G_i ribosylation is an important step in the activation of L-arginine transport by PTX. An activator of adenylate cyclase, forskolin, and an activator of protein kinase A (PKA), Sp-cAMPS, did not affect L-arginine transport in PAEC. In addition, inhibitors of PKA or adenylate cyclase did not change the activating effect of PTX on L-arginine uptake. Long-term treatment with PTX (18 h) induced a 40% decrease in protein kinase C (PKC)- but did not affect the activities of PKC- and PKC- in PAEC. An activator of PKC-, phorbol 12-myristate 13-acetate, abrogated the activation of L-arginine transport in PAEC treated with PTX. Incubation of PTX-treated PAEC with phorbol 12-myristate 13-acetate in combination with an inhibitor of PKC- (Go 6976) restored the activating effects of PTX on L-arginine uptake, suggesting PTX-induced activation of L-arginine transport is mediated through downregulation of PKC-. Measurements of nitric oxide (NO) production by PAEC revealed that long-term treatment with PTX induced twofold increases in the amount of NO in PAEC. PTX also increased L-[³H]citrulline production from extracellular L-[³H]arginine without affecting endothelial NO synthase activity. These results demonstrate that PTX increased NO production through activation of L-arginine transport in PAEC.

cationic amino acid transporter; regulation; G proteins; caveolae; protein kinase C-

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