Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice

被引:141
作者
Zwart, R
Verhaagh, S
Buitelaar, M
Popp-Snijders, C
Barlow, DP
机构
[1] Netherlands Canc Inst, Dept Mol Genet H5, NL-1066 CX Amsterdam, Netherlands
[2] Free Univ Amsterdam, Dept Endocrinol, NL-1007 MB Amsterdam, Netherlands
关键词
D O I
10.1128/MCB.21.13.4188-4196.2001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Two uptake systems that control the extracellular concentrations of released monoamine neurotransmitters such as noradrenaline and adrenaline have been described. Uptake-1 is present at presynaptic nerve endings, whereas uptake-2 is extraneuronal and has been identified in myocardium and vascular and nonvascular smooth muscle cells. The gene encoding the uptake-2 transporter has recently been identified in humans (EMT), rats (OCT3), and mice (Orct3/Slc22a3). To generate an in vivo model for uptake-2, we have inactivated the mouse Orct3 gene. Homozygous mutant mice are viable and fertile with no obvious physiological defect nd also show no significant imbalance of noradrenaline or dopamine. However, Orct3-null mice show an impaired uptake-2 activity as measured by accumulation of intravenously administered [H-3]MPP+ (1-methyl-4-phenylpyridinium). A 72% reduction in MPP+ levels was measured in hearts of both male and female Orct3 mutant mice. No significant differences between wild-type and mutant mice were found in any other adult organ or in plasma. When [H-3]MPP+ was injected into pregnant females, a threefold-reduced MPP+ accumulation was observed in homozygous mutant embryos but not in their placentas or amniotic fluid. These data show that Orct3 is the principal component for uptake-2 function in the adult heart and identify the placenta as a novel site of action of uptake-2 that acts at the fetoplacental interface.
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页码:4188 / 4196
页数:9
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