Journal
JOURNAL OF MOLECULAR NEUROSCIENCE
Volume 52, Issue 3, Pages 425-433Publisher
HUMANA PRESS INC
DOI: 10.1007/s12031-013-0171-9
Keywords
TRPC1; HT22 cells; Glutamate; Cell death
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Funding
- German Research Foundation [SFB636/A5]
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Transient receptor potential channel 1 (TRPC1; a cation channel activated by store depletion and/or through an intracellular messenger) is expressed in a variety of tissues, including the brain. To study the physiological function of TRPC1, we investigated the role of endogenously expressed TRPC1 in glutamate-induced cell death, using the murine hippocampal cell line HT22. Knocking down TRPC1 mRNA using TRPC1-shRNA or blocking of TRPC channels using 2-APB (a parts per thousand yen200 mu M) robustly attenuated glutamate-induced cell death after 24 h of incubation with 5 mM glutamate. Glutamate toxicity in HT22 cells seems to involve metabotropic glutamate receptor mGluR5 since MPEP (2-methyl-6-(phenylethynyl)-pyridine), an mGluR5 antagonist (a parts per thousand yen100 mu M), abrogated glutamate toxicity. Furthermore, a direct activation of mGluR5 by CHPG [(RS)-chloro-5-hydroxyphenylglycine; 100 mu M or 300 mu M] promoted HT22 cell death. TRPC1 knock-down markedly reduced CHPG-induced cell death. These observations suggest that glutamate-induced cell death in HT22 cells activates mGluR5 receptors, which significantly increases Ca2+ influx through TRPC1 channels. TRPC1 knock-down prevented glutamate- and CHPG-induced cell death, suggesting that glutamate-induced toxicity in HT22 cells is mediated through TRPC1 channels and an mGluR5-dependent pathway. Together, this work provides evidence for a novel receptor activation pathway of TRPC1 in glutamate-induced toxicity.
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