A missense mutation in kynurenine aminotransferase-1 in spontaneously hypertensive rats.
Spontaneously hypertensive rats (SHR) are the most extensively used animal model for genetic hypertension, increased stroke damage, and insulin resistance syndromes; however, the identification of target genes has proved difficult. SHR show elevated sympathetic nerve activity, and stimulation of the central blood pressure control centers with glutamate or nicotine results in exaggerated blood pressure responses, effects that appear to be genetically determined. Kynurenic acid, a competitive glutamate antagonist and a non-competitive nicotinic antagonist, can be synthesized in the brain by the enzyme kynurenine aminotransferase-1 (KAT-1). We have previously shown that KAT-1 activity is significantly reduced in SHR compared with normotensive Wistar Kyoto rats (WKY). Here we show that KAT-1 contains a missense mutation, E61G, in all the strains of SHR examined but not in any of the WKY or outbred strains. Previous studies on F2 rats from a cross of stroke-prone SHR and WKY have shown a suggestive level of linkage between elevated blood pressure and the KAT-1 locus on chromosome 3. In addition, the mutant enzyme expressed in Escherichia coli displays altered kinetics. This mutation may explain the enhanced sensitivity to glutamate and nicotine seen in SHR that may be related to an underlying mechanism of hypertension and increased sensitivity to stroke.
Kwok
John B J
JB
Garvan Institute of Medical Research, Sydney, 2010 Australia.
Kapoor
Ranjna
R
Gotoda
Takanari
T
Iwamoto
Yasuhiko
Y
Iizuka
Yoko
Y
Yamada
Nobuhiro
N
Isaacs
Kim E
KE
Kushwaha
Virag V
VV
Church
W Bret
WB
Schofield
Peter R
PR
Kapoor
Vimal
V
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000378:metabolism; D007700:Kinetics; D007736:Kynurenic Acid / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D000637:Transaminases / Q000235:genetics*
D018076:DNA, Complementary; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid