Acceleration of serotonin transporter transport-associated current by 3,4-methylenedioxymethamphetamine (MDMA) under acidic conditions.
3,4-Methylenedioxymethamphetamine (MDMA) selectively releases serotonin (5-HT) from neurons after uptake by the serotonin transporter (SERT) and causes psychostimulant effects accompanied by hyperthermia. Since rapid increases in CNS lactate levels are suggested in response to MDMA, we investigated the effects of the physiologically-relevant increase in H(+) concentration on the two conducting states of SERT expressed in Xenopus oocytes. Perfusion with SERT substrates at pH 7.4 dose-dependently evoked a transport-associated inward current response with the following rank order of potency: 5-HT>MDMA>dopamine>>norepinephrine. In the absence of transport substrates, a step hyperpolarization pulse activated a transient Na(+) leak current, which was inhibited by SERT substrates with the same rank, as well as by a SERT inhibitor, citalopram. At pH 6.4, the K(m) values of 5-HT and dopamine for the transport-associated current were not altered, while that of MDMA was three-fold lower. In contrast, the K(i) values of all these substrates for transient leak current were unchanged at pH 6.4, suggesting that the affinities to SERT binding sites are not influenced. These results suggest that the effect of MDMA on SERT is enhanced by acidic conditions.
Yamauchi
Yosuke
Y
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Izumi
Takaya
T
Unemura
Kazuhiro
K
Uenishi
Yoshie
Y
Nakagawa
Takayuki
T
Kaneko
Shuji
S
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D009865:Oocytes; D011522:Protons; D051381:Rats; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis
D011522:Protons; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D015222:Sodium Channels; D012701:Serotonin; D019344:Lactic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D009638:Norepinephrine