Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine‐NMDA receptor‐mediated neuronal cell death

• Published in: Journal of neurochemistry 2013-02, Vol.124 (4), p.558-570
• Main Authors: Poddar, Ranjana, Paul, Surojit
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Calcium - metabolism; Caspase 3 - metabolism; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Cerebral Cortex - cytology; crosstalk; Dose-Response Relationship, Drug; Embryo, Mammalian; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; ERK mitogen‐activated protein kinase; Excitatory Amino Acid Agents - pharmacology; Extracellular Signal-Regulated MAP Kinases - metabolism; Green Fluorescent Proteins - genetics; Homocysteine; Homocysteine - metabolism; Homocysteine - pharmacology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Neurochemistry; Neurological disorders; neuronal cell death; Neurons - drug effects; NMDA; p38 Mitogen-Activated Protein Kinases - metabolism; p38 mitogen‐activated protein kinase; Phosphorylation - drug effects; Rats; Receptors, N-Methyl-D-Aspartate - metabolism; RNA Interference - physiology; Transfection
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12102

Hyperhomocysteinemia is an independent risk factor for both acute and chronic neurological disorders, but little is known about the underlying mechanisms by which elevated homocysteine can promote neuronal cell death. We recently established a role for NMDA receptor‐mediated activation of extracellular signal‐regulated kinase (ERK)‐MAPK in homocysteine‐induced neuronal cell death. In this study, we examined the involvement of the stress‐induced MAPK, p38 in homocysteine‐induced neuronal cell death, and further explored the relationship between the two MAPKs, ERK and p38, in triggering cell death. Homocysteine‐mediated NMDA receptor stimulation and subsequent Ca2+ influx led to a biphasic activation of p38 MAPK characterized by an initial rapid, but transient activation followed by a delayed and more prolonged response. Selective inhibition of the delayed p38 MAPK activity was sufficient to attenuate homocysteine‐induced neuronal cell death. Using pharmacological and RNAi approaches, we further demonstrated that both the initial and delayed activation of p38 MAPK is downstream of, and dependent on activation of ERK MAPK. Our findings highlight a novel interplay between ERK and p38 MAPK in homocysteine‐NMDA receptor‐induced neuronal cell death. Hyperhomocysteinemia is an independent risk factor for neurological disorders. We report here that homocysteine‐NMDA receptor mediated neuronal death involves a novel interplay between ERK and p38 MAPK where activation of p38 MAPK is downstream of and dependent on ERK MAPK. The direct regulatory role of ERK MAPK in p38 MAPK activation reveals a previously unidentified cellular mechanism for neuronal cell death.