One of the main instigators leading to cell death and brain damage following ischemia is Ca2+ dysregulation. Neuronal membrane depolarization results in the activation of voltage-gated Ca2+ (Ca-V) channels and intracellular Ca2+ influx. We investigated the physiological role of the Ca(V)2.1 (P/Q-type) channel in ischemic neuronal injury using Ca(V)2.1 channel alpha(l) 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 24 h 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 Ca2+ imaging study, oxygen-glucose deprivation using a hippocampal slice induced a significantly slower rate of increase in intracellular Ca2+ concentration ([Ca2+]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 Ca(V)2.1 channel in rolling Nagoya and leaner mice plays a different protective role in a ([Ca2+]i)l-dependent manner in ischemic models and indicate that Ca(V)2.1 channel blockers may be used preventively against ischemic injury. (C) 2013 Elsevier Inc. All rights reserved.