Analysis of ischemic neuronal injury in Cav2.1 channel α1 subunit mutant mice
Xiaoli Tian1, Ying Zhou, Linghan Gao
1Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1690, USA.
Abstract:
One of the main instigators leading to cell death and brain damage following ischemia is Ca(2+) dysregulation. Neuronal membrane depolarization results in the activation of voltage-gated Ca(2+) (CaV) channels and intracellular Ca(2+) influx. We investigated the physiological role of the CaV2.1 (P/Q-type) channel in ischemic neuronal injury using CaV2.1 channel α1 subunit mutant mice, rolling Nagoya and leaner mice. The in vivo ischemia model with a complete occlusion of the middle cerebral artery showed that the infarct area at 24h was significantly smaller in rolling Nagoya (27.1±3.5% of total brain volume) and leaner (20.1±3.5%) mice compared to wild-type (42.9±4.5%) mice. In an in vitro Ca(2+) imaging study, oxygen-glucose deprivation using a hippocampal slice induced a significantly slower rate of increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in rolling Nagoya (0.083±0.007/min) and leaner (0.062±0.006/min) mice compared to wild-type (0.105±0.008/min) mice. These results demonstrate that the mutant CaV2.1 channel in rolling Nagoya and leaner mice plays a different protective role in a ([Ca(2+)]i)-dependent manner in ischemic models and indicate that CaV2.1 channel blockers may be used preventively against ischemic injury.
Insights
Mutant CaV2.1 channels protect against brain damage from stroke. These findings suggest CaV2.1 channel blockers could prevent ischemic injury by regulating intracellular calcium levels.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Calcium ion (Ca2+) dysregulation is a key factor in cell death and brain damage after ischemia.
- Neuronal depolarization activates voltage-gated Ca2+ (CaV) channels, leading to intracellular Ca2+ influx.
Purpose of the Study:
- To investigate the physiological role of the CaV2.1 (P/Q-type) channel in ischemic neuronal injury.
- To explore the protective mechanisms of mutant CaV2.1 channels in ischemic conditions.
Main Methods:
- Utilized CaV2.1 channel α1 subunit mutant mice (rolling Nagoya and leaner) in an in vivo middle cerebral artery occlusion model.
- Performed in vitro Ca2+ imaging studies using hippocampal slices subjected to oxygen-glucose deprivation.
Main Results:
- In vivo ischemia models showed significantly smaller infarct volumes in rolling Nagoya and leaner mice compared to wild-type mice (20.1–27.1% vs. 42.9%).
- In vitro studies revealed a slower rate of intracellular Ca2+ concentration increase in mutant mice during oxygen-glucose deprivation (0.062–0.083/min vs. 0.105/min).
Conclusions:
- Mutant CaV2.1 channels confer a protective role in ischemic injury through a Ca2+-dependent mechanism.
- CaV2.1 channel blockers show potential as a preventive treatment against ischemic brain damage.
