Type

Journal Article

Authors

Jochen H M Prehn
Heiko Düssmann
David C Henshall
Tobias Engel
Nikolaus Plesnila
Shona Pfeiffer
Helena P Bonner
Sergio Perez Alvarez
Gang Chen
Seán M Kilbride
and 2 others

Subjects

Biochemistry

Topics
neurons physics pathology deficiency embryo mice inbred c57bl cell line tumor n methylaspartate cell death tumor embryo mammalian inbred c57bl anoxia mitochondria calcium transgenic neocortex physiology pharmacology animals glucose bcl 2 associated x protein mammalian cells cultured homeostasis mice cytology drug effects cell line mice transgenic cells extracellular fluid excitatory amino acid agonists ultrastructure bax protein mouse calcium signaling cultured endoplasmic reticulum genetics metabolism

Bax regulates neuronal Ca2+ homeostasis. (2015)

Abstract Excessive Ca(2+) 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(2+) and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca(2+) transients during the NMDA excitation period and did not exhibit the deregulation of Δψm that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca(2+) dynamics during NMDA excitation, suggesting that Bax controlled Ca(2+) signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca(2+) levels using FRET-based sensors indicated that the effects of bax deficiency on Ca(2+) handling were not due to enhanced cellular bioenergetics or increased Ca(2+) uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca(2+)-induced permeability transition. However, when Ca(2+) uptake into the sarco/endoplasmic reticulum was blocked with the Ca(2+)-ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca(2+) levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca(2+) handling is critical for cell death signaling during periods of neuronal overexcitation.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed
Ireland -> Royal College of Surgeons in Ireland -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

Jochen H M Prehn, Heiko Düssmann, David C Henshall, Tobias Engel, Nikolaus Plesnila, Shona Pfeiffer, Helena P Bonner, Sergio Perez Alvarez, Gang Chen, Seán M Kilbride and 2 others

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heiko Düssmann
Royal College of Surgeons in Ireland
Total Publications: 45
 
3
David C Henshall
Royal College of Surgeons in Ireland
Total Publications: 127
 
4
Tobias Engel
Royal College of Surgeons in Ireland
Total Publications: 66
 
5
Nikolaus Plesnila
Royal College of Surgeons in Ireland
Total Publications: 9
 
6
Shona Pfeiffer
Royal College of Surgeons in Ireland
Total Publications: 14
 
7
Helena P Bonner
Royal College of Surgeons in Ireland
Total Publications: 15
 
8
G Chen
Royal College of Surgeons in Ireland
Total Publications: 19