Glutamate transport and cellular glutamine metabolism: regulation in LLC-PK1 vs. LLC-PK1-F+cell lines

Author:

Meade Dale1,Chess Catherine1,Welbourne Tomas C.1

Affiliation:

1. Department of Cellular and Molecular Physiology, Louisiana State University Medical Center in Shreveport, Shreveport, Louisiana 71130-3932

Abstract

The glutamate (Glu) transporter may modulate cellular glutamine (Gln) metabolism by regulating both the rates of hydrolysis and subsequent conversion of Glu to α-ketoglutarate and[Formula: see text]. By delivering Glu, a competitive inhibitor of Gln for the phosphate-dependent glutaminase (PDG) as well as an acid-load activator of glutamate dehydrogenase (GDH) flux, the transporter may effectively substitute extracellularly generated Glu from the γ-glutamyltransferase for that derived intracellularly from Gln. We tested this hypothesis in two closely related porcine kidney cell lines, LLC-PK1 and LLC-PK1-F+, the latter selected to grow in the absence of glucose, relying on Gln as their sole energy source. Both cell lines exhibited PDG suppression as the result of Glu uptake while disrupting the extracellularl-Glu uptake, withd-aspartate-accelerated intracellular Glu formation coupled primarily to the ammoniagenic pathway (GDH). Conversely, enhancing the extracellular Glu formation with p-aminohippurate and Glu uptake suppressed intracellular Gln hydrolysis while[Formula: see text] formation from Glu increased. Thus these results are consistent with the transporter’s dual role in modulating both PDG and GDH flux. Interestingly, PDG flux was actually higher in the Gln-adapted LLC-PK1-F+cell line because of a two- to threefold enhancement in Gln uptake despite greater Glu uptake than in the parental LLC-PK1 cells, revealing the importance of both Glu and Gln transport in the modulation of PDG flux. Nevertheless, when studied at physiological Gln concentration, PDG flux falls under tight Glu transporter control as Gln uptake decreases, suggesting that cellular Gln metabolism may indeed be under Glu transporter control in vivo.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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