title: Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+).
abstract: N-Methyl-D-aspartate receptors (NMDA receptors) are known to be permeable to Na(+) and Ca(2+) ions. In this study, we tested whether polyamines (putrescine, spermidine, spermine), organic cations found in cells, can permeate NMDA receptors expressed in Xenopus laevis oocytes and HEK293 cells. It was found that polyamines, especially spermidine, can permeate NMDA channels expressed from GluN1/GluN2A or GluN1/GluN2B activated by glycine and glutamate. Furthermore, spermidine and Ca(2+) influx through NMDA receptors was observed in the presence of Mg(2+), although Na(+) influx was strongly inhibited by Mg(2+). The Km values for spermidine influx through GluN1/GluN2A and GluN1/GluN2B were 2.2 mM and 2.7 mM, respectively in the presence of isotonic extracellular ion solutions. Spermidine uptake by NMDA receptors was dependent on the presence of glycine and glutamate, and inhibited by Ca(2+) and by memantine, an NMDA receptor channel blocker. The Km values for Ca(2+) influx through GluN1/GluN2A and GluN1/GluN2B were 4.6 mM and 3.3 mM, respectively, under the same ionic conditions. The results indicate that spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors in the presence of Mg(2+). Spermidine, if released locally from presynaptic terminals (where its concentration is high in synaptosomes and synaptic vesicles) could permeate NMDA receptors and play a role in synaptic plasticity mediated by NMDA receptors together with Ca(2+).
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Hirose
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan; Amine Pharma Research Institute, Innovation Plaza at Chiba University, Chiba, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Saiki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yoshizawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Higashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Itsuko
authors.initials: I
authors.lastname: Ishii
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toida
authors.affiliation: Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Williams
authors.affiliation: Faculty of Pharmacy, Chiba Institute of Science, Choshi, Chiba, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kashiwagi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan; Amine Pharma Research Institute, Innovation Plaza at Chiba University, Chiba, Japan. Electronic address: iga16077@faculty.chiba-u.jp.
authors.forename: Kazuei
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010539:Permeability; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000145:classification / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012964:Sodium; D008274:Magnesium; D002118:Calcium; D013095:Spermidine
keywords: Importance of Mg(2+); NMDA receptors; Na(+) uptake inhibition; Spermidine and Ca(2+) uptake; Synaptic plasticity