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Caveolin‐1 is essential for NMDAR localization to membrane rafts and NMDAR‐mediated activation of Src and ERK1/2 in primary neurons
Author(s) -
Head Brian Patrick,
Patel Hemal H.,
Tsutsumi Yasuo M.,
Insel Paul A.,
Roth David M.,
Patel Piyush M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1180.6
Subject(s) - nmda receptor , lipid raft , microbiology and biotechnology , caveolin 1 , kinase , proto oncogene tyrosine protein kinase src , mapk/erk pathway , chemistry , caveolin , biology , neurotoxicity , phosphorylation , signal transduction , neuroscience , receptor , caveolae , biochemistry , organic chemistry , toxicity
N‐methyl‐D‐aspartate receptor (NMDAR) signaling is important for neuronal synaptic plasticity, learning and memory. Downstream activation of pro‐survival Src family kinases and ERK1/2 (extracellular‐regulated signal kinase) is initiated by NMDAR activation but little is known about the cellular organization of these kinases in relation to the NMDAR. We hypothesized that caveolin‐1 compartmentalizes protein complexes necessary for NMDAR signaling in discrete microdomains. We found that sub‐lethal ischemia (SLI) or pharmacological preconditioning via NMDA treatment of primary cortical neurons increases phosphorylated caveolin‐1 (P‐caveolin‐1), P‐Src, and P‐ERK1/2. Primary neurons treated with caveolin‐1 siRNA lacked NMDA‐mediated increase in P‐Src and P‐ERK and neuronal preconditioning was not observed. Basally, NMDAR2B (NR2B) was present in both buoyant fractions (BF) and heavy fractions (HF) from wild type (WT) neurons. Exposure of neurons to NMDA redistributed NR2B to HF only. In caveolin‐1 −/− neurons, under basal conditions NR2B was only present in HF. Adenoviral expression of caveolin‐1 ( Adv‐Cav1 ) in caveolin‐1 −/− neurons resulted in the detection of NR2B in both BF and HF, and exposure of these neurons to NMDA redistributed NR2B to HF only. In caveolin‐1 −/− neurons, NMDA treatment failed to increase P‐Src and P‐ERK. Adv‐Cav1 treated neurons from caveolin‐1 −/− mice resulted in NMDA‐mediated enhancement of P‐Src and P‐ERK1/2. We conclude that caveolin‐1 protein expression is essential for localization of NR2B to membrane rafts and subsequent NMDAR‐mediated signaling in primary neurons. (Supported by NIH)