Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice.
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 [(3)H]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 [(3)H]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.
Zwart
R
R
Department of Molecular Genetics (H5), The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Verhaagh
S
S
Buitelaar
M
M
Popp-Snijders
C
C
Barlow
D P
DP
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D018390:Gene Targeting; D006540:Herbicides / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D027701:Organic Cation Transport Proteins; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D000099254:Organic Cation Transporter 3
D015655:1-Methyl-4-phenylpyridinium; D015306:Biogenic Monoamines; D002352:Carrier Proteins; D006540:Herbicides; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3