Homer1/mGluR1-mediated ER stress contributes to lysophosphatidic acid-induced neurotoxicity in cortical neurons.
Neurochem Int
; 129: 104515, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31369778
ABSTRACT
Lysophosphatidic acid (LPA) is a glycerophospholipid that can be detected in serum, saliva and cerebrospinal fluid. However, the effect of LPA on neuronal death and survival has not been fully determined. In the present study, we investigated the potential neurotoxic effect of LPA in primary cultured cortical neurons. Treatment with LPA (0.5, 1 and 5⯵M) markedly decreased neuronal viability, increased lactate dehydrogenase (LDH) release and promoted apoptosis in cortical neurons. The results of western blot showed that LPA increased the expression of endoplasmic reticulum (ER) stress associated factors, and the protein misfolding inhibitor 4-phenylbutyric acid (4-PBA) attenuated LPA-induced toxicity. In addition, treatment with LPA did not alter the expression and distribution of Homer1 in cortical neurons. The protein levels of metabotropic glutamate receptor 1 (mGluR1), but not metabotropic glutamate receptor 5 (mGluR5), were significantly increased by LPA at 12 and 24â¯h after treatment. Knockdown of Homer1 using specific siRNA partially prevented the LPA-induced neurotoxicity and ER stress. Furthermore, the results of Ca2+ imaging showed that treatment with LPA induced intracellular Ca2+ release, which could be partially prevented by 4-PBA and downregulation of Homer1. The LPA-induced intracellular Ca2+ release was associated with ER Ca2+ release through the Homer1-mGluR1 pathway. In summary, our results showed that LPA treatment induced ER stress and apoptosis in cortical neurons, and its neurotoxicity was partially mediated by Ca2+ release from the ER via the Homer1/mGluR1 pathway.
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Base de dados:
MEDLINE
Assunto principal:
Lisofosfolipídeos
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Transdução de Sinais
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Receptores de Glutamato Metabotrópico
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Sinalização do Cálcio
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Estresse do Retículo Endoplasmático
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Proteínas de Arcabouço Homer
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Proteínas do Tecido Nervoso
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Neurônios
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article