Substance P regulation of glutamate and cystine transport in human astrocytoma cells.
UC11 human astrocytoma cells transported glutamate by at least two distinct systems which appeared to be very similar to the Na(+)-dependent XAG- system (glutamate and aspartate are preferred substrates) and the Na(+)-independent xc- system (glutamate and cystine are preferred substrates) described in other cells, including primary cultures of rat astrocytes. The xc- system accounted for about 80% of the total glutamate influx. In a Na(+)-free buffer, the average Km and Vmax values for glutamate influx in UC11 cells were 167 +/- 15 microM and 0.82 +/- 0.04 nmoles/min/mg protein. Substance P, acting via an NK1 receptor, caused half maximal inhibition of glutamate and cystine transport at a peptide concentration of approximately 3 nM. Maximal inhibition was usually in the range of 60-80% and was noncompetitive in nature. Substance P also induced a significant increase in the release of endogenous glutamate. These effects of Substance P may be of pathophysiological significance in the CNS: first, a combination of inhibition of glutamate influx and stimulation of glutamate efflux from astrocytes is potentially toxic with respect to nearby neurons; second, an inhibition of cystine influx could result in a depletion of intracellular glutathione, resulting in increased sensitivity to oxidative stress.
Johnson
C L
CL
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio 45267-0575.
Johnson
C G
CG
D001254:Astrocytoma / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects; D003553:Cystine / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D006801:Humans; D007700:Kinetics; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D005971:Glutamates; D018040:Receptors, Neurokinin-1; D013373:Substance P; D018698:Glutamic Acid; D003553:Cystine; D012964:Sodium