TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons.
Transient receptor potential vanilloid 1 (TRPV1) functions as a polymodal nociceptor and is activated by several vanilloids, including capsaicin, protons and heat. Although TRPV1 channels are widely distributed in the brain, their roles remain unclear. Here, we investigated the roles of TRPV1 in cytotoxic processes using TRPV1-expressing cultured rat cortical neurons. Capsaicin induced severe neuronal death with apoptotic features, which was completely inhibited by the TRPV1 antagonist capsazepine and was dependent on extracellular Ca(2+) influx. Interestingly, nifedipine, a specific L-type Ca(2+) channel blocker, attenuated capsaicin cytotoxicity, even when applied 2-4 h after the capsaicin. ERK inhibitor PD98059 and several antioxidants, but not the JNK and p38 inhibitors, attenuated capsaicin cytotoxicity. Together, these data indicate that TRPV1 activation triggers apoptotic cell death of rat cortical cultures via L-type Ca(2+) channel opening, Ca(2+) influx, ERK phosphorylation, and reactive oxygen species production.
Shirakawa
Hisashi
H
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Yamaoka
Tomoko
T
Sanpei
Kazuaki
K
Sasaoka
Hirotoshi
H
Nakagawa
Takayuki
T
Kaneko
Shuji
S
D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000613:Aminobutyrates; D000975:Antioxidants; D020746:Calcium Channels, L-Type; D005419:Flavonoids; C401954:N(gamma)-acetyl-2,4-diaminobutyric acid; D017382:Reactive Oxygen Species; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D002211:Capsaicin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium