Lead-Induced ERK Activation Is Mediated by GluR2 Non-containing AMPA Receptor in Cortical Neurons

• Published in: Biological & pharmaceutical bulletin 2017/03/01, Vol.40(3), pp.303-309
• Main Authors: Ishida, Keishi, Kotake, Yaichiro, Sanoh, Seigo, Ohta, Shigeru
• Format: Article
• Language: English
• Subjects: 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; Animals; Brain - cytology; Brain - drug effects; Calcium; Calcium - metabolism; Calcium permeability; Cell death; Cells, Cultured; Central nervous system; Dizocilpine; Environmental Pollutants - adverse effects; Excitatory Amino Acid Antagonists - pharmacology; Excitotoxicity; Exposure; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; glutamate receptor 2; Glutamic Acid - metabolism; Glutamic acid receptors (ionotropic); Kinases; lead; Lead - adverse effects; Lead Poisoning, Nervous System - metabolism; MAP kinase; mitogen-activated protein kinase (MAPK); N-Methyl-D-aspartic acid receptors; Neurons - drug effects; Neurons - metabolism; Neurotoxicity; p38 Mitogen-Activated Protein Kinases - metabolism; Pollutants; Protein kinase C; Protein Kinase C - metabolism; Protein Subunits; Proteins; Rats; Receptors, AMPA - metabolism; Spermine; Toxicity; Vulnerability; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b16-00784

Lead is a persistent environmental pollutant and exposure to high environmental levels causes various deleterious toxicities, especially to the central nervous system (CNS). The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor that is devoid of the glutamate receptor 2 (GluR2) subunit is Ca2+-permeable, which increases the neuronal vulnerability to excitotoxicity. We have previously reported that long-term exposure of rat cortical neurons to lead acetate induces decrease of GluR2 expression. However, it is not clarified whether lead-induced GluR2 decrease is involved in neurotoxicity. Therefore, we investigated the contribution of GluR2 non-containing AMPA receptor to lead-induced neurotoxic events. Although the expression of four AMPA receptor subunits (GluR1, GluR2, GluR3, and GluR4) was decreased by lead exposure, the decrease in GluR2 expression was remarkable among four subunits. Lead-induced neuronal cell death was rescued by three glutamate receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a non-selective AMPA receptor blocker), MK-801 (N-methyl-D-aspartate (NMDA) receptor blocker), and 1-naphthyl acetyl spermine (NAS, a specific Ca2+-permeable AMPA receptor blocker). Lead exposure activated extracellular signal-regulated protein kinase (ERK) 1/2, which was significantly ameliorated by CNQX. In addition, lead exposure activated p38 mitogen-activated protein kinase (MAPK p38), and protein kinase C (PKC), which was partially ameliorated by CNQX. Our findings indicate that Ca2+-permeable AMPA receptors resulting from GluR2 decrease may be involved in lead-induced neurotoxicity.