Signalling pathways initiated by AAs contribute to the control of cell physiology during altered nutrient availability. We have analysed the pathways that enhance expression of the System A amino acid transporter SNAT2 during AA deprivation in L6 myotubes. Inhibitors of PI-3-kinase, GSK3 and JNK impair the increase in SNAT2 expression typically observed during AA lack.

AA withdrawal stimulated JNK phosphorylation in a manner dependent upon GSK3 activity and a model is presented whereby an AA-sensitive pathway from GSK3 to MEKK1, SEK and JNK controls SNAT2 transcription. In complementary studies, the nature of the AA sensor(s) that regulate SNAT2 expression were assessed in the light of a long standing hypothesis: that the System A carrier functions as both a transporter and an AA sensor (transceptor). Consistent with this, natural System A substrates prevented upregulation of System A and SNAT2 expression, with the AA concentration required to repress SNAT2 reflecting that required for extracellular binding by SNAT2. However, at concentrations which do not interact with the transporter, the aromatic amino acids also impaired System A adaptation. Aromatic AA and a subset of the System A substrates (Gln>Ser>Ala) were found to inhibit JNK phosphorylation and it is proposed that the SNAT2 transceptor functions in parallel with a second, JNK regulating, AA receptor to control SNAT2 transcription during nutritional stress.