Role of TRP channels and NCX in mediating hypoxia-induced [Ca(2+)](i) elevation in PC12 cells.

Abstract

Mammalian cells require a constant O2 supply to produce adequate energy, and sustained hypoxia can kill cells. Mammals therefore have evolved sophisticated mechanisms to allow their cells to adapt to hypoxia. In this study, we investigated the role of TRP channels and the Na+-Ca2+ exchanger (NCX) in mediating hypoxia-induced [Ca2+]i elevation in a model of the O2-sensing rat pheochromocytoma (PC12) cell line by using Ca2+ imaging and molecular biological approaches. Non-selective cation channels, such as TRPC1, 3 and 6, were found to be functionally expressed in PC12 cells. They mediated Ca2+ entry when cells were exposed to acute hypoxia (PO2 of 15 mmHg), in addition to Ca2+ entry via VGCCs. Blockage of TRPCs by 2APB and SKF96365 could significantly reduce hypoxia-mediated [Ca2+]i elevation. Suramin and U73122 attenuated the hypoxia-induced [Ca2+]i elevation, implying the involvement of the G-protein and PLC pathways in the hypoxic response. In addition to TRPCs and VGCCs, NCX also contributed to the hypoxia-induced [Ca2+]i elevation, and blockade of NCX by KBR7943 could significantly decrease the hypoxia-induced [Ca2+]i elevation. Our results suggest that the activation of TRP by hypoxia could lead to NCX reversal; furthermore, membrane depolarization and TRPCs may play a primary role in mediating the hypoxic response in PC12 cells.

• Authors: Fei Meng, Wilson King Lim To, Yuchun Gu
• Journal: Respiratory physiology & neurobiology (Respir Physiol Neurobiol) Vol. 164 Issue 3 Pg. 386-93 (Dec 31 2008) ISSN: 1569-9048 [Print] Netherlands
• PMID: 18822394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
• Boron Compounds
• Calcium Channel Blockers
• Imidazoles
• Sodium-Calcium Exchanger
• TRPC Cation Channels
• Suramin
• Potassium Chloride
• Verapamil
• 2-aminoethoxydiphenyl borate
• Thiourea
• 1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
• Calcium

Topics

• Animals
• Boron Compounds (pharmacology)
• Calcium (metabolism)
• Calcium Channel Blockers
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Hypoxia (metabolism, physiopathology)
• Imidazoles (pharmacology)
• Models, Biological
• PC12 Cells (drug effects, metabolism)
• Potassium Chloride (pharmacology)
• Rats
• Sodium-Calcium Exchanger (antagonists & inhibitors, physiology)
• Suramin (pharmacology)
• TRPC Cation Channels (genetics, metabolism)
• Thiourea (analogs & derivatives, pharmacology)
• Verapamil (pharmacology)