Behavioral changes following antisense oligonucleotide-induced reduction of organic cation transporter-3 in mice

Kitaichi, Kiyoyuki; Fukuda, Makoto; Nakayama, Haruhiko; Aoyama, Nagisa; Ito, Yukiko; Fujimoto, Yohei; Takagi, Kenji; Takagi, Kenzo; Hasegawa, Takaaki

doi:10.1016/j.neulet.2005.03.014

Cited by 53 publications

(43 citation statements)

References 19 publications

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“…Reduced Oct3 protein expression after antisense oligonucleotide administration to mice is associated with markedly higher methamphetamine-induced locomotor activity. Enhanced locomotor activity is probably due to reduced clearance of monoaminergic neurotransmitters, and thus more neuronal stimulation (Kitaichi et al, 2005). Likewise, brains from Oct3-null mice exhibit higher extracellular dopamine concentrations and greater loss of striatal nerve terminals after methamphetamine administration compared with wild type (Cui et al, 2009a).…”

Section: Uptake Transporters In Brainmentioning

confidence: 99%

“…Likewise, brains from Oct3-null mice exhibit higher extracellular dopamine concentrations and greater loss of striatal nerve terminals after methamphetamine administration compared with wild type (Cui et al, 2009a). Based on the observed altered methamphetamine handling in mice with reduced expression of Oct3 (Kitaichi et al, 2005), the allelic frequencies of SLC22A3 (OCT3) polymorphisms were determined in 213 Japanese subjects with methamphetamine dependence (Aoyama et al, 2006). Two intronic variants were associated with the development of polysubstance abuse in this population (Aoyama et al, 2006).…”

Section: Uptake Transporters In Brainmentioning

confidence: 99%

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Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

2010

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Section: Uptake Transporters In Brainmentioning

confidence: 99%

Section: Uptake Transporters In Brainmentioning

confidence: 99%

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

2010

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“…The surplus of electric charge flowing through OCT2 may increase and/or prolong depolarization at axosomatic cholinergic or serotonergic synapses. OCT3 participates in reuptake of epinephrine, norepinephrine, and histamine and is involved in modulation of motor activity, behavior, and regulation of salt uptake (16,30). It is presently unknown whether this OCT subtype also exhibits voltage-dependent variation of charge-to-substrate ratio, but such properties would be equally important for the role of OCT3 in brain function.…”

Section: Technical Aspectsmentioning

confidence: 99%

Charge-to-substrate ratio during organic cation uptake by rat OCT2 is voltage dependent and altered by exchange of glutamate 448 with glutamine

Schmitt¹,

Gorbunov²,

Schlachtbauer³

et al. 2009

American Journal of Physiology-Renal Physiology

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Schmitt BM, Gorbunov D, Schlachtbauer P, Egenberger B, Gorboulev V, Wischmeyer E, Mü ller T, Koepsell H. Charge-tosubstrate ratio during organic cation uptake by rat OCT2 is voltage dependent and altered by exchange of glutamate 448 with glutamine. Am J Physiol Renal Physiol 296: F709 -F722, 2009. First published February 11, 2009 doi:10.1152/ajprenal.90323.2008.-Uptake of substrate and electric charge was measured simultaneously in voltageclamped Xenopus laevis oocytes expressing rat organic cation transporter 2 (rOCT2). At 0 mV, saturating substrate concentrations induced uptake of more positive elementary charges than monovalent organic cations, with charge-to-substrate ratios of 1.5 for guanidinium ϩ , 3.5 for tetraethylammonium ϩ , and 4.0 for 1-methyl-4-phenylpyridinium ϩ . At negative holding potentials, the charge-tosubstrate ratios decreased toward unity. At 0 mV, charge-to-substrate ratios higher than unity were observed at different extracellular pH and after replacement of extracellular Na ϩ , K ϩ , Ca 2ϩ , Mg 2ϩ , and/or Cl Ϫ . Charge-to-substrate ratios were not influenced by intracellular succinate 2Ϫ or glutarate 2Ϫ . The effects of membrane potential and ion substitution strongly suggest that the surplus of transported positive charge is not generated by passive ion permeabilities. Rather, we hypothetize that small cations are taken up together with organic cation substrates whereas the outward reorientation of the empty transporter is electroneutral. Nonselective cotransport of small cations was supported by the three-dimensional structures of rOCT2 in its inward-facing and outward-facing conformations, which we determined by homology modeling based on known corresponding structures of H ϩ -lactose permease of E. coli, and by functional analysis of OCT mutants. In our model, the innermost cavity of the outward-open binding cleft is negatively charged by Glu448 and Asp475, whereas the inward-open innermost cavity is electroneutral, containing Asp379, Asp475, Lys215, and Arg440. Substitution of Glu448 by glutamine reduced the charge-to-TEA ϩ ratio at 0 mV to unity. The observed charge excess associated with organic cation uptake into depolarized cells may contribute to tubular damage in renal failure. organic cation uptake; kidney; stoichiometry; charge translocation; membrane potential ORGANIC CATION TRANSPORTERS (OCTs) of the SLC22 family translocate a wide range of structurally diverse molecules (17, 18). They participate in small intestinal uptake, hepatic excretion and/or renal excretion of various endogenous and exogenous compounds, including choline, monoamine neurotransmitters, coenzymes, and drugs or xenobiotics. The cloning of rat OCT1 (rOCT1) (12) and the subsequent identification of other members of the SLC22 family, including OCT2, which is mainly expressed in the kidney, and OCT3, which has a broad tissue distribution including brain, has led to a much better understanding of these transporters. Particular progress has been made in elucidating their functional characteristics, tiss...

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“…OCT3 could transport METH [39] and is likely to be an important transporter in the elimination of xenobiotics and endogenous waste from extracellular areas and cerebrospinal fluid (CSF) [21]. Very recently, we have found that WIS rats with induced BS by repeated METH administration, show decreased expression of OCT3 in the brain [16,18]. According to these findings, OCT3 could regulate the influx/efflux of METH in the brain by transporting METH from CSF into blood circulation and/or by uptake of METH from extracellular areas into cells expressing OCT3 [21].…”

Section: Introductionmentioning

confidence: 99%