Activation of classical protein kinase C decreases transport via systems y+ and y+L.

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Rotmann A, Simon A, Martine U, Habermeier A, Closs EI

Activation of classical protein kinase C decreases transport via systems y+ and y+L.

Am J Physiol Cell Physiol. 2007 Jun;292(6):C2259-68. Epub 2007 Feb 28.

PubMed ID

17329401 [ View in PubMed

]

Abstract

Activation of protein kinase C (PKC) downregulates the human cationic amino acid transporters hCAT-1 (SLC7A1) and hCAT-3 (SLC7A3) (Rotmann A, Strand D, Martine U, Closs EI. J Biol Chem 279: 54185-54192, 2004; Rotmann A, Vekony N, Gassner D, Niegisch G, Strand D, Martine U, Closs EI. Biochem J 395: 117-123, 2006). However, others found that PKC increased arginine transport in various mammalian cell types, suggesting that the expression of different arginine transporters might be responsible for the opposite PKC effects. We thus investigated the consequence of PKC activation by phorbol-12-myristate-13-acetate (PMA) in various human cell lines expressing leucine-insensitive system y(+) [hCAT-1, hCAT-2B (SLC7A2), or hCAT-3] as well as leucine-sensitive system y(+)L [y(+)LAT1 (SLC7A7) or y(+)LAT2 (SLC7A6)] arginine transporters. PMA reduced system y(+) activity in all cell lines tested, independent of the hCAT isoform expressed, while mRNAs encoding the individual hCAT isoforms were either unchanged or increased. System y(+)L activity was also inhibited by PMA. The extent and onset of inhibition varied between cell lines; however, a PMA-induced increase in arginine transport was never observed. In addition, when expressed in Xenopus laevis oocytes, y(+)LAT1 and y(+)LAT2 activity was reduced by PMA, and this inhibition could be prevented by the PKC inhibitor bisindolylmaleimide I. In ECV304 cells, PMA-induced inhibition of systems y(+) and y(+)L could be prevented by Go6976, a specific inhibitor of conventional PKCs. Thymelea toxin, which activates preferentially classical PKC, had a similar inhibitory effect as PMA. In contrast, phosphatidylinositol-3,4,5-triphosphate-dipalmitoyl, an activator of atypical PKC, had no effect. These data demonstrate that systems y(+) and y(+)L are both downregulated by classical PKC.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Arginine	Cationic amino acid transporter 3	Protein	Humans	Unknown	Not Available	Details
Arginine	Cationic amino acid transporter 4	Protein	Humans	Unknown	Not Available	Details
Arginine	High affinity cationic amino acid transporter 1	Protein	Humans	Unknown	Not Available	Details

Polypeptides

Name	UniProt ID
Y+L amino acid transporter 1	Q9UM01	Details
Y+L amino acid transporter 2	Q92536	Details