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Vol. 54, Issue 4, 601-609, October 1998
Departments of
Pharmacology (L.D.J., S.A., M.D.M., E.W., R.D.B.)
and
Cell Biology (D.M.M.) and
Center for Molecular Neuroscience
(D.M.M., R.D.B.),
Vanderbilt University School of Medicine, Nashville
TN 37232-6600 and Fort Dodge Animal Health, Princeton, New Jersey
08543-0400 (M.E.)
A small subset of neurons in the nematode Caenorhabditis
elegans utilizes the catecholamine dopamine (DA) as a
neurotransmitter to control or modulate movement and egg-laying.
Disruption of DA-mediated behaviors represents a potentially powerful
strategy to identify genes that are likely to participate in
dopaminergic systems in man. In vertebrates, extracellular DA is
inactivated by presynaptic DA transport proteins (DATs) that are also
major targets of addictive agents, including amphetamines and cocaine. We used oligonucleotides derived from the C.
elegans genomic locus T23G5.5 to isolate and characterize
T23G5.5 cDNAs. Our studies predict that mRNAs from this locus encode a
615-amino-acid polypeptide with twelve stretches of hydrophobicity
suitable for transmembrane domains, similar to that found in vertebrate
catecholamine transporters. The inferred translation product bears
highest identity (43-47%) to catecholamine (DA, norepinephrine,
epinephrine) transporters within the
GAT1/NET gene family and possesses
conserved residues implicated in amine substrate recognition.
Consistent with these findings, HeLa cells transfected with the
C. elegans cDNA exhibit saturable and
high affinity DA transport (Km = 1.2 µM) that is dependent on extracellular
Na+ and Cl
and blocked by inhibitors of
mammalian catecholamine transporters, including norepinephrine
transporter- and DAT-selective antagonists, tricyclic antidepressants,
and the nonselective amine transporter antagonists cocaine and
D-amphetamine. These studies validate the
T23G5.5 locus as encoding a functional
catecholamine transporter, providing important comparative sequence
information for catecholamine transporter structure/function studies
and a path to identify regulators of dopaminergic signaling via genetic
or pharmacologic manipulation of C.
elegans cDNA in vivo.
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