Amino acids involved in differences in the pharmacological profiles of the rat and human noradrenaline transporters

Naunyn-Schmiedeberg's Archives of Pharmacology
F A Paczkowski, Lesley J Bryan-Lluka

Abstract

It has been suggested from a previous study in our laboratory that differences in the pharmacology of the species variants of the noradrenaline transporter (NET) are the result of four non-conservative amino acid exchanges from the total of 26 amino acids that are divergent between the rat NET (rNET) and human NET (hNET). The aim of this study was to examine the effects of changing the rNET at each of these four amino acid residues, which markedly alter local charge distribution, to the amino acid found in hNET.Site-directed mutagenesis was used to create mutant cDNAs from rNET cDNA. The mutant NETs (rK7D, rE62K, rK375N and rR612Q), rNET and hNET were expressed in transiently transfected COS-7 cells to determine the effects of the mutations on the differing pharmacological properties of the species variants. The ratios of V(max) for noradrenaline uptake and B(max) for nisoxetine binding (which are a measure of the turnover number of the transporter, i.e. the number of transport cycles per min) were greater for rNET and rR612Q than for hNET, rK7D, rE62K and rK375N. The K(m) of noradrenaline was lower for hNET, rK7D, rE62K and rK375N than for rNET or rR612Q. There were no differences between the K(i) values for inhibition of nora...Continue Reading

Citations

Nov 13, 2003·European Journal of Pharmacology·David L RomanEric L Barker
Jan 13, 2006·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Motoyasu YamashitaIchiro Sora
Jun 27, 2009·Chemical Communications : Chem Comm·Jacob AndersenKristian Strømgaard

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