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Molecular and Cellular Biology, July 2001, p. 4188-4196, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4188-4196.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Impaired Activity of the Extraneuronal Monoamine Transporter System Known as Uptake-2 in Orct3/Slc22a3-Deficient Mice

Ronald Zwart,1 Sandra Verhaagh,1 Marije Buitelaar,1 Corrie Popp-Snijders,2 and Denise P. Barlow1,*

Department of Molecular Genetics (H5), The Netherlands Cancer Institute, 1066 CX Amsterdam,1 and Department of Endocrinology, Free University, 1007 MB Amsterdam,2 The Netherlands

Received 23 February 2001/Returned for modification 15 March 2001/Accepted 13 April 2001

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 and 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 [3H]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 [3H]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.

* Corresponding author. Present address: ÖAW Institute of Molecular Biology, Billrothstrasse 11, A-5020 Salzburg, Austria. Phone: 43 662 63 961 14. Fax: 43 662 63 961 40. E-mail: dbarlow{at}imb.oeaw.ac.at.

Molecular and Cellular Biology, July 2001, p. 4188-4196, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4188-4196.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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