Regulation of the Cav1.2 cardiac channel by redox via modulation of CaM interaction with the channel

• Main Authors: Yu Sun, Jianjun Xu, Etsuko Minobe, Shoken Shimoara, Liying Hao, Masaki Kameyama
• Format: Article
• Language: English
• Published: Elsevier 2015-07-01
• Series: Journal of Pharmacological Sciences
• Subjects: Redox; Cav1.2 channel; Calmodulin; Cardiac myocyte; Ion channel regulation
• Online Access: http://www.sciencedirect.com/science/article/pii/S1347861315001097

Although it has been well documented that redox can modulate Cav1.2 channel activity, the underlying mechanisms are not fully understood. In our study, we examined the effects of redox on Cav1.2 channel activity and on CaM interaction with the Cav1.2 α1 subunit. Dithiothreitol (DTT, 1 mM) in the cell-attached mode decreased, while hydrogen peroxide (H2O2, 1 mM) increased channel activity to 72 and 303%, respectively. The effects of redox were maintained in the inside-out mode where channel activity was induced by CaM + ATP: DTT (1 mM) decreased, while H2O2 (1 mM) increased the channel activity. These results were mimicked by the thioredoxin and oxidized glutathione system. To test whether the redox state might determine channel activity by affecting the CaM interaction with the channel, we examined the effects of DTT and H2O2 on CaM binding to the N- and C-terminal fragments of the channel. We found that DTT concentration-dependently inhibited CaM binding to the C-terminus (IC50 37 μM), but H2O2 had no effect. Neither DTT nor H2O2 had an effect on CaM interaction with the N-terminus. These results suggest that redox-mediated regulation of the Cav1.2 channel is governed, at least partially, by modulation of the CaM interaction with the channel.