title: New insights into the mechanism of neurolathyrism: L-β-ODAP triggers [Ca2+]i accumulation and cell death in primary motor neurons through transient receptor potential channels and metabotropic glutamate receptors.
abstract: Neurolathyrism is a motor neuron (MN) disease caused by β-N-oxalyl-L-α,β-diaminopropionic acid (L-β-ODAP), an AMPA receptor agonist. L-β-ODAP caused a prolonged rise of intracellular Ca(2+) ([Ca(2+)]i) in rat spinal cord MNs, and the [Ca(2+)]i accumulation was inversely proportional to the MN's life span. The [Ca(2+)]i rise induced by L-β-ODAP or (S)-AMPA was antagonized completely by NBQX, an AMPA-receptor blocker. However, blocking the L-type Ca(2+) channel with nifedipine significantly lowered [Ca(2+)]i induced by (S)-AMPA, but not that by L-β-ODAP. Tetrodotoxin completely extinguished the [Ca(2+)]i rise induced by (S)-AMPA or kainic acid, whereas that induced by L-β-ODAP was only attenuated by 65.6±6% indicating the prominent involvement of voltage-independent Ca(2+) entry. The tetrodotoxin-resistant [Ca(2+)]i induced by L-β-ODAP was blocked by 2-APB, Gd(3+), La(3+), 1-(β-[3-(4-methoxy-phenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SKF-96365) and flufenamic acid, which all are blockers of the transient receptor potential (TRP) channels. Blockers of group I metabotropic glutamate receptors (mGluR I), 7-(hydroxyiminocyclopropan[b]chromen-1α-carboxylate ethyl ester (CPCCPEt) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) also lowered the [Ca(2+)]i rise by L-β-ODAP. MN cell death induced by L-β-ODAP was prolonged significantly with SKF-96365 as well as NBQX. The results show the involvement of TRPs and mGluR I in L-β-ODAP-induced MN toxicity through prolonged [Ca(2+)]i mobilization, a unique characteristic of this neurotoxin.
authors.affiliation: Laboratory of Biochemistry, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan; Laboratory of Molecular Cell Biology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Kusama-Eguchi
authors.affiliation: Laboratory of Molecular Cell Biology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miyano
authors.affiliation: Laboratory of Molecular Cell Biology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan; Laboratory of Pharmacology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Molecular Cell Biology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Suda
authors.affiliation: Laboratory of Pharmacology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Laboratory of Pharmacology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ishige
authors.affiliation: Laboratory of Biochemistry, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Laboratory of Molecular Cell Biology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Laboratory of Molecular Cell Biology, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Center for Environment, Health and Field Sciences, Chiba University, Kashiwanoha 6-2-1, Kashiwa 277-0822, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Ikegami
authors.affiliation: Laboratory of Physiology and Anatomy, School of Pharmacy, Nihon University, Narashinodai 7-7-1, Funabashi 274-8555, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kusama
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D005260:Female; D007842:Lathyrism / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: C510363:3-N-oxalyl-L -2,3-diaminopropanoic acid; D018094:Receptors, Metabotropic Glutamate; D050051:Transient Receptor Potential Channels; D015091:beta-Alanine; D002118:Calcium
keywords: Ca(2+) imaging; Group I metabotropic glutamate receptor; L-β-ODAP; Motor neuron; Neurolathyrism; TRP channels