Regulation of dopamine and MPP+ transport by catecholamine transporters.
Following exocytotic release of the biogenic amine neurotransmitters, norepinephrine and dopamine, are removed from the synaptic cleft by the respective transporter, norepinephrine transporter (NET) and dopamine transporter (DAT) located on the plasma membrane. The catecholamine transporters are the molecular targets for psychoactive drugs as well as drugs of abuse such as cocaine and amphetamine and the Parkinsonism-inducing neurotoxin, MPP+. Nicotine regulates the transport of catecholamines and MPP+ and may exert self-medicating effects for depression, schizophrenia and attention deficit hyperactivity disorder, and neuroprotective effects against MPP+ through the regulation of the transporters. The availability of cDNAs of these transporters has permitted detailed pharmacological studies in heterologous expression systems for determining the mechanisms of action of nicotine on transporters. Moreover, functional analysis of the effect of single amino acid substitution suggests that specific residues in DAT molecules may play a significant role in interaction with MPP+ and cocaine, and thus would promise a development of novel drugs with diverse chemical structures.
Dohi
Toshihiro
T
Department of Dental Pharmacology, Division of Integrated Medical Science, Hiroshima University Graduate School of Biomedical Sciences, Kasumi, Minami-ku, Hiroshima 734-8553.
Kitayama
Shigeo
S
Morioka
Norimitsu
N
Kumagai
Kei
K
Mitsuhata
Chieko
C
Morita
Katsuya
K
Kozai
Katsuyuki
K
Lin
Zhicheng
Z
Uhl
George R
GR
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000502:physiology*; D050482:Catecholamine Plasma Membrane Transport Proteins; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D026901:Membrane Transport Proteins; D009538:Nicotine / Q000494:pharmacology*
D002352:Carrier Proteins; D050482:Catecholamine Plasma Membrane Transport Proteins; D026901:Membrane Transport Proteins; D009538:Nicotine; D003042:Cocaine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine