Calcium Entry through L-type Calcium Channels Causes Mitochondrial Disruption and Chromaffin Cell Death

Abstract

] m and caused mitochondrial membrane depolarization. Cyclosporin A, a blocker of the mitochondrial transition pore, and superoxide dismutase prevented the apoptotic cell death induced by Ca 2؉ overload through L-channels. These results suggest that Ca 2؉ entry through L-channels causes both calcium overload and mitochondrial disruption that will lead to the release of mediators responsible for the activation of the apoptotic cascade and cell death. This predominant role of L-type Ca 2؉ channels is not shared by other subtypes of high threshold voltage-dependent neuronal Ca 2؉ channels (i.e. N, P/Q) expressed by bovine chromaffin cells.

Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

“…Taking into account that compound ITH12505 has kept most of the neuroprotective activity against cell Ca 2+ deregulation-derived excitoxicity found in the parental compound CGP37157, the VDCC blocking activity by ITH12505 has been studied, using the Ca 2+ -sensitive fluorescent dye Fluo-4/AM on SH-SY5Y cells, stimulating Ca nimodipine (Nimo) was used as reference. 3 The same experiment was carried out with CGP37157. Compound ITH12505 blocked K + -induced Ca 2+ entry in a concentrationdependent manner, with a maximum at 100 μM, where Ca 2+ entry was reduced to 12% (Figure 8a).…”

“…34 Actually, first evidence of a mNCX blockade was found in VDCC blockers, such as diltiazem, prenylamine, fendiline, nifedipine, or verapamil. 55,56 The altered Ca 2+ influx through VDCCs, preferentially via Ltype (Ca v 1.1−1.4), has been reported to be a key mechanism of neuronal death occurring in several physiopathological events, 3 such as neurodegenerative processes. Taking into account that compound ITH12505 has kept most of the neuroprotective activity against cell Ca 2+ deregulation-derived excitoxicity found in the parental compound CGP37157, the VDCC blocking activity by ITH12505 has been studied, using the Ca 2+ -sensitive fluorescent dye Fluo-4/AM on SH-SY5Y cells, stimulating Ca nimodipine (Nimo) was used as reference.…”

“…2 The observation that not only high Ca 2+ overload 3 but also Ca 2+ antagonists, 4 reducing [Ca 2+ ] c , can cause neuronal death, has raised the hypothesis that Ca 2+ ions behave as both cell survival supporters and cell death promoters, depending on both amplitude and temporal extension of the cell Ca 2+ signal, together with other physiological conditions. 5 Hence, there has to be a critical set point where Ca 2+ -derived cytoprotective signals might turn into cytotoxic.…”

3,4-Methylenedioxymethamphetamine enhances kainic acid convulsive susceptibility

“…The entry of calcium into neurons is strongly associated with seizures (Meyer, 1989;McNamara, 1992) and the sustained entry induces excitotoxicity, leading to alterations of mitochondria and subsequent cell death (Cano-Abad et al, 2001). CaBP are crucial for calcium homeostasis in neurons (Baimbridge et al, 1992 Prior to the experiments about calcium levels, we confirmed that the MDMA concentrations used (10-100 µM) have no effect on cortical cell viability (calcein assay 48 h: saline 100.00 ± 2.61%, MDMA 100 µM 107.98 ± 3.79%, n.s.…”

CALHM1 and its polymorphism P86L differentially control Ca2+ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

“…Accumulated evidence suggests that AD is also linked to an imbalance of intracellular Ca 2+ homeostasis (Bezprozvanny & Mattson, 2008; Green & LaFerla, 2008; Marambaud et al ., 2009; Fernandez‐Morales et al ., 2012), because Ca 2+ plays a critical role in maintaining cell survival; for example, a mild elevation of [Ca 2+ ] c promotes neuronal survival and plasticity, whereas more pronounced elevations can cause neurotoxicity (Berridge et al ., 1998; Cano‐Abad et al ., 2001). Thus, alterations in Ca 2+ homeostatic mechanisms associated with aging, mutations in amyloid precursor protein (APP) and presenilins, and dysfunctional Ca 2+ fluxes at the endoplasmic reticulum (ER) can promote neuronal cell death (Bezprozvanny & Mattson, 2008).…”