Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

Abstract

Calcium homeostasis modulator 1 (CALHM1) is a calcium channel involved in the regulation of cytosolic Ca 2+ 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 ([Ca 2+ ]) ions. At low [Ca 2+ ] e or depolarization, the channel is opened, allowing Ca 2+ influx; however, high extracellular [Ca 2+ ] e or hyperpolarization promote its resting state. The unique Ca 2+ permeation of CALHM1 relates to the molecular events that take place in brain ischemia, such as depolarization and extracellular changes in [Ca 2+ ] 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.Cells 2020, 9, 664 2 of 13 plasminogen activator (rt-PA), has limitations [3][4][5]. During ischemic stroke, 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].The drop in blood flow triggers a decrease of oxygen and glucose supply in the infarct area, promoting a disruption in the electron transport chain that leads to mitochondrial failure and a reduction of ATP levels. This decrease in ATP induces the malfunctioning of different membrane pumps such as Na + /K + /ATPase and Ca 2+ /ATPase, promoting membrane depolarization due to Na + influx. This depolarization provokes the opening of voltage-dependent calcium channels (VDCCs) and makes the Na + /Ca 2+ exchanger work in its reverse way; these two processes lead to intracellular Ca 2+ overload [7,8]. This massive entry of Ca 2+ into the neurons induces glutamate excitotoxicity, triggers the production of reactive oxygen species (ROS), and the release of inflammatory cytokines that ultimately lead to neuronal death [9][10][11][12]. Therefore, maintenance of intracellular Ca 2+ homeostasis is crucial for cellular survival and function [11].Consider...

Interrelation between ROS and Ca2+ in aging and age-related diseases

“…Besides, depletion of the Ca 2+ homeostasis modulator 1 (CALHM1), a Ca 2+ channel involved in the regulation of cytosolic Ca 2+ levels, was found to downregulate ROS production, to increase the expression of HIF-1α and to display neuroprotective effects against ischemia in mice [ 164 ]. Notably, the mutation of this channel (P86L-CALHM1) got associated with Alzheimer's disease and mitochondrial Ca 2+ overload, potentially causing increased vulnerability of these cells to apoptotic stimuli [ [165] , [166] , [167] ].…”

Thermosensitivity of the voltage-dependent activation of calcium homeostasis modulator 1 (calhm1) ion channel

“…Their multimeric assembly forms unselective ion channel with large pore structure, activated by membrane depolarization [1,2]. In mice, its knockout ( calhm1 −/− ) impaired the long-term potentiation of hippocampal neurons [3], and a pathological role has been suggested in the ischemia-reperfusion injury of brain [4]. The expression of calhm1 has been also confirmed in taste buds, the nasal epithelium and the bladder, acting as a voltage-gated ATP-release channel [5–7].…”

Synthesis and study of spectrally diagnosed heterocyclic compound

“…The other studies (Mahajan et al, 2020;Mahajan and Badarla, 2019) where technology plays the signi icant roles have been reviewed during this work. Apart from this, we have studied several other recent methods (Garrosa et al, 2020;Moustafa et al, 2019) across the different domains where the chemical compositions analyzed by considering real-time applications.…”