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

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Abstract
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 mouseOrct3 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 Orct3is 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.