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Acidosis-Sensing Glutamine Pump SNAT2 Determines Amino Acid Levels and Mammalian Target of Rapamycin Signalling to Protein Synthesis in L6 Muscle Cells

Kate Evans^*, Zeerak Nasim^*, Jeremy Brown^*, Heather Butler^*, Samira Kauser^*, Hélène Varoqui, Jeffrey D. Erickson, Terence P. Herbert and Alan Bevington^*

^* Department of Infection, Immunity and Inflammation, University of Leicester, John Walls Renal Unit, Leicester General Hospital, and Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom; and Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana

Address correspondence to: Dr. Alan Bevington, Department of Infection, Immunity and Inflammation, University of Leicester, John Walls Renal Unit, Leicester General Hospital, Leicester LE5 4PW, UK. Phone: +44-116-258-8041; Fax: +44-116-273-4989; E-mail: ab74{at}leicester.ac.uk

Received for publication September 15, 2006. Accepted for publication February 19, 2007.

Wasting of lean tissue as a consequence of metabolic acidosis is a serious problem in patients with chronic renal failure. A possible contributor is inhibition by low pH of the System A (SNAT2) transporter, which carries the amino acid L-glutamine (L-Gln) into muscle cells. The aim of this study was to determine the effect of selective SNAT2 inhibition on intracellular amino acid profiles and amino acid–dependent signaling through mammalian target of rapamycin in L6 skeletal muscle cells. Inhibition of SNAT2 with the selective competitive substrate methylaminoisobutyrate, metabolic acidosis (pH 7.1), or silencing SNAT2 expression with small interfering RNA all depleted intracellular L-Gln. SNAT2 inhibition also indirectly depleted other amino acids whose intracellular concentrations are maintained by the L-Gln gradient across the plasma membrane, notably the anabolic amino acid L-leucine. Consequently, SNAT2 inhibition strongly impaired signaling through mammalian target of rapamycin to ribosomal protein S6 kinase, ribosomal protein S6, and 4E-BP1, leading to impairment of protein synthesis comparable with that induced by rapamycin. It is concluded that even though SNAT2 is only one of several L-Gln transporters in muscle, it may determine intracellular anabolic amino acid levels, regulating the amino acid signaling that affects protein mass, nucleotide/nucleic acid metabolism, and cell growth.

This article has been cited by other articles:

				K. Evans, Z. Nasim, J. Brown, E. Clapp, A. Amin, B. Yang, T. P. Herbert, and A. Bevington Inhibition of SNAT2 by Metabolic Acidosis Enhances Proteolysis in Skeletal Muscle J. Am. Soc. Nephrol., November 1, 2008; 19(11): 2119 - 2129. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673