Abstract
Calcium homeostasis modulator 1 (CALHM1) is a calcium channel involved in the regulation of cytosolic Ca2+ levels. From a physiological point of view, the open state of CALHM1 depends not only on voltage but also on the extracellular concentration of calcium ([Ca2+]) ions. At low [Ca2+]e or depolarization, the channel is opened, allowing Ca2+ influx; however, high extracellular [Ca2+]e or hyperpolarization promote its resting state. The unique Ca2+ permeation of CALHM1 relates to the molecular events that take place in brain ischemia, such as depolarization and extracellular changes in [Ca2+]e, particularly during the reperfusion phase after the ischemic insult. In this study, we attempted to understand its role in an in vitro model of ischemia, namely oxygen and glucose deprivation, followed by reoxygenation (OGD/Reox). To this end, hippocampal slices from wild-type Calhm1+/+, Calhm1+/−, and Calhm1−/− mice were subjected to OGD/Reox. Our results point out to a neuroprotective effect when CALHM1 is partially or totally absent. Pharmacological manipulation of CALHM1 with CGP37157 reduced cell death in Calhm1+/+ slices but not in that of Calhm1−/− mice after exposure to the OGD/Reox protocol. This ionic protection was also verified by measuring reactive oxygen species production upon OGD/Reox in Calhm1+/+ and Calhm1−/− mice, resulting in a downregulation of ROS production in Calhm1−/− hippocampal slices and increased expression of HIF-1α. Taken together, we can conclude that genetic or pharmacological inhibition of CALHM1 results in a neuroprotective effect against ischemia, due to an attenuation of the neuronal calcium overload and downregulation of oxygen reactive species production.
Highlights
Ischemic stroke is the most frequent cause of cerebrovascular disease [1]
Hippocampal slices from Calhm1+/+, Calhm1+/− and Calhm1−/− mice were subjected to the oxygen and glucose deprivation (OGD)/Reox protocol previously described
Considering the high Ca2+ permeability of Calcium homeostasis modulator 1 (CALHM1), and the excessive release of this cation to the synaptic cleft during an ischemic insult, it is presumable that the lack of the channel exerts a beneficial effect against ischemic damage
Summary
Ischemic stroke is the most frequent cause of cerebrovascular disease [1] It is the third leading cause of death and the main cause of adult disability worldwide. Despite this high unmet medical need, there is no current effective neuroprotective treatment [2]. The acute occlusion of a vessel produces a rapid central core of brain infarct tissue where cells suffer necrosis. This core area is surrounded by a hypoxic but potentially salvageable tissue—the ischemic penumbra, where the blood flow reduction is not so drastic [6]
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