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Vol. 54, Issue 2, 342-352, August 1998
Institut für Physiologie, 72076 Tübingen, Germany
(A.E.B., C.B., S.W., F.L.),
Anatomisches Institut, 97070 Würzburg, Germany (U.K., D.M., V.G., A.A., C.V., P.A., J.C.U.,
H.K.), and
Vollum Institute, Portland, Oregon 97201 (M.S.S.)
Recently, we cloned the human cation transporter hOCT2, a member of a
new family of polyspecific transporters from kidney, and demonstrated
electrogenic uptake of tetraethylammonium, choline, N1-methylnicotinamide, and 1-methyl-4-phenylpyridinium.
Using polymerase chain reaction amplification, cDNA sequencing,
in situ hybridization, and immunohistochemistry, we now
show that hOCT2 message and protein are expressed in neurons of the
cerebral cortex and in various subcortical nuclei. In Xenopus
laevis oocytes expressing hOCT2, electrogenic transport of
norepinephrine, histamine, dopamine, serotonin, and the
antiparkinsonian drugs memantine and amantadine was demonstrated by
tracer influx, tracer efflux, electrical measurements, or a
combination. Apparent Km values
of 1.9 ± 0.6 mM (norepinephrine), 1.3 ± 0.3 mM (histamine), 0.39 ± 0.16 mM (dopamine), 80 ± 20 µM
(serotonin), 34 ± 5 µM (memantine), and
27 ± 3 µM (amantadine) were estimated.
Measurement of trans-effects in depolarized oocytes and
human embryonic kidney cells expressing hOCT2 suggests that there
were different rates and specificities for cation influx and
efflux. The hypothesis is raised that hOCT2 plays a physiological role
in the central nervous system by regulating interstitial concentrations
of monoamine neurotransmitters that have evaded high affinity uptake
mechanisms. We show that amantadine does not interact with the
expressed human Na+/Cl
dopamine
cotransporter. However, concentrations of amantadine that are effective
for the treatment of Parkinson's disease may increase the interstitial
concentrations of dopamine and other aminergic neurotransmitters by
competitive inhibition of hOCT2.
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