title: MKC-231, a choline uptake enhancer: (3) Mode of action of MKC-231 in the enhancement of high-affinity choline uptake.
abstract: MKC-231, a putative cholinergic activity, is reported to improve learning and memory impaired in AF64A-treated animals. MKC-231 enhances high-affinity choline uptake (HACU) known as the rate-limiting step of acetylcholine (ACh) synthesis. We investigated the mode of action (MOA) of HACU enhancement by MKC-231. Intracerebroventricular (i.c.v.) injections of AF64A (3 nmol/brain) resulted in significant HACU reduction in hippocampal synaptosomes. Treatment with MKC-231 increased Vmax of HACU and Bmax of [3H]-HC-3 binding 1.6 and 1.7-fold, respectively. In studies of [3H]-MKC-231 binding and Biacore analysis, MKC-231 showed noticeable affinity for cloned high-affinity choline transporters (CHT1). The present study suggests that MKC-231 directly affects trafficking of CHT1 and increases the numbers of transporter, working for HACU, at the synaptic membrane.
authors.affiliation: Pharmacology Department IV, Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. takashina.ken@mh.mt-pharma.co.jp
authors.forename: Ken
authors.initials: K
authors.lastname: Takashina
authors.forename: Tomoko
authors.initials: T
authors.lastname: Bessho
authors.forename: Reiko
authors.initials: R
authors.lastname: Mori
authors.forename: Kunji
authors.initials: K
authors.lastname: Kawai
authors.forename: Junichi
authors.initials: J
authors.lastname: Eguchi
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Saito
mesh_terms: D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D002794:Choline / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004347:Drug Interactions; D006426:Hemicholinium 3 / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism*; D014162:Transfection; D014316:Tritium / Q000378:metabolism
chemical_list: D001388:Aziridines; D026901:Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D011804:Quinolines; C065637:choline transporter; D014316:Tritium; D006426:Hemicholinium 3; C044894:ethylcholine aziridinium; D002794:Choline; C092988:MKC 231