Bax Regulates Neuronal Ca²⁺Homeostasis

Abstract

Excessive Ca 2ϩ entry during glutamate receptor overactivation ("excitotoxicity") induces acute or delayed neuronal death. We report here that deficiency in bax exerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca 2ϩ and mitochondrial membrane potential (⌬ m ) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca 2ϩ transients during the NMDA excitation period and did not exhibit the deregulation of ⌬ m that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca 2ϩ dynamics during NMDA excitation, suggesting that Bax controlled Ca 2ϩ signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca 2ϩ levels using FRET-based sensors indicated that the effects of bax deficiency on Ca 2ϩ handling were not due to enhanced cellular bioenergetics or increased Ca 2ϩ uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca 2ϩ -induced permeability transition. However, when Ca 2ϩ uptake into the sarco/endoplasmic reticulum was blocked with the Ca 2ϩ -ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca 2ϩ levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca 2ϩ handling is critical for cell death signaling during periods of neuronal overexcitation.

Expression of MICU1 after experimental focal cerebral ischemia in adult rats

“…Scale bar = 100 μm Previous studies showed that a rise of calcium concentration signals an increased cellular energy demand and mediates a number of pathways that can precipitate mitochondrial injury and cell death [9]. Of interest, increments in [Ca 2+ ] c are detected at the acute phases after MCAO [10][11][12]. At approximately the same time, the expression of MCU is up-regulated [13].…”

THE ROLE OF ANTI-APOPTIC PROTEIN Bcl-2 IN DEVELOPMENT OF DRUG RESISTANCE IN CHILDREN WITH LOCALIZATION-RELATED EPILEPSY

“…Важно отметить, что гиперпродукция белка Bcl-2 у детей с ло-кально обусловленной эпилепсией направлена на стабилизацию кальциевого гомеостаза. Было показано, что увеличение концентрации белка Bcl-2 предотвращает выход внутриклеточного кальция из эндоплазматического ретикулума, усиливая его обратный захват, а также потенци-рует увеличение пассивного транспорта кальция в митохондрии и ингибирует вхождение ионов кальция в ядро [10,19]. Следовательно, высокая активность окислительных процессов у больных ДЦП и существующая кальций-зависимая ги-первозбудимость при эпилепсии создают усло-вия для повышенного синтеза белка Bcl-2.…”

“…Изучены молекулярные механиз-мы, с помощью которых белки семейства Вс1-2 регулируют апоптоз: это митохондриальный путь и процесс активации каспаз [7,8,9]. Известно, что белок Bcl-2 участвует в поддержании кле-точного гомеостаза ионов кальция, регулируя по-ток кальция через эндоплазматический ретику-лум [10,11]. Несмотря на то, что ключевая роль в регуляции апоптоза для онкогена Bcl-2 уста-новлена давно и не вызывает сомнения [12], мо-лекулярный механизм действия этого антиапоп-тотического белка при эпилепсии не выяснен.…”

Neuroprotection of Sesamin against Cerebral Ischemia In-Vivo and N-Methyl-D-Aspartate-Induced Apoptosis In-Vitro

“…However, excessive glutamate is associated with numerous neurological disorders including stroke, traumatic brain injury [2,3], multiple sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease [4]. Excessive glutamate can over activate glutamate receptors and result in high calcium ion (Ca 2+ ) influx, which activates a number of enzymes that damage cell structures such as the cell membrane, cytoskeleton components and DNA.…”

“…Caspase-3, a member of the caspase family, determines the incidence of apoptosis. The members of the Bcl-2 family such as Bcl-2 and Bax proteins are the most prominent factors in the mitochondria-mediated apoptotic pathway [3,9]. Studies have shown the powerful properties of various natural polyphenols against neuronal exitotoxicity induced by NMDA [10,11].…”