Calcium-induced permeability transition in rat brain mitochondria is promoted by carbenoxolone through targeting connexin43

Azarashvili, Tamara; Baburina, Yulia; Grachev, Dmitry; Krestinina, Olga; Evtodienko, Yu. V.; Stricker, Rolf; Reiser, Georg

doi:10.1152/ajpcell.00061.2010

Cited by 46 publications

(48 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data showed that Cbx altered the parameters of mPTP function by shortening the lag time of MPT onset (lowering the capacity to retain Ca 2+ in the matrix) and initiating Ca 2+ -induced Ca 2+ efflux from the mitochondrial matrix [6]. Cbx increased Ca 2+ -induced high amplitude swelling of both RBM and RLM.…”

Section: Introductionmentioning

confidence: 96%

“…Recently, we compared the mechanism of action of Cbx on Ca 2+ -induced mPTP opening in rat brain mitochondria (RBM, synaptic and non-synaptic) and rat liver mitochondria (RLM), in an attempt to identify the mitochondrial target of Cbx [6]. Our data showed that Cbx altered the parameters of mPTP function by shortening the lag time of MPT onset (lowering the capacity to retain Ca 2+ in the matrix) and initiating Ca 2+ -induced Ca 2+ efflux from the mitochondrial matrix [6].…”

Section: Introductionmentioning

confidence: 99%

“…Cbx increased Ca 2+ -induced high amplitude swelling of both RBM and RLM. Cbx-stimulated Ca 2+ efflux and Ca 2+ -induced high amplitude swelling of mitochondria were CsA sensitive [6]. These effects of Cbx were not linked to ROS production, however, connexin43 (Cx43) was identified to be the target of Cbx [6].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, we detected Cx43 in rat brain and heart mitochondria, but not in liver mitochondria. However, Cx26 and Cx32 were found in rat liver mitochondria and may also be targets for Cbx [6]. …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Carbenoxolone induces permeability transition pore opening in rat mitochondria via the translocator protein TSPO and connexin43

Azarashvili

Baburina

Grachev

et al. 2014

Archives of Biochemistry and Biophysics

Self Cite

View full text Add to dashboard Cite

Ca2+-induced permeability transition pore (mPTP) opening in isolated rat brain mitochondria is promoted through targeting of connexin43. After a threshold Ca2+ load, mitochondrial membrane potential drops and efflux of accumulated Ca2+ from the mitochondrial matrix occurs, indicating the mPTP opening. Specific antibodies were used to assess the role of the translocator protein (18 kDa; TSPO) and connexin43 in swelling of isolated rat liver and brain mitochondria induced by carbenoxolone and the endogenous TSPO ligand protoporphyrin IX. Mitochondrial membrane potential, Ca2+ transport and oxygen consumption were determined using selective electrodes. All the parameters were detected simultaneously in a chamber with the selective electrodes. The phosphorylation state of mitochondrial protein targets was assessed. We report that Ca2+-induced mitochondrial swelling was strengthened in the presence of both carbenoxolone and protoporphyrin IX. The carbenoxolone- and protoporphyrin IX-accelerated mPTP induction in brain mitochondria was completely prevented by antibodies specific for the mitochondrial translocator protein (TSPO). The anti-TSPO antibodies were more effective than anti-connexin43 antibodies. Moreover, carbenoxolone-stimulated phosphorylation of mitochondrial proteins was inhibited by anti-TSPO antibodies. Taken together, the data suggests that, in addition to acting via connexion43, carbenoxolone may exert its effect on mPTP via mitochondrial outer membrane TSPO.

show abstract

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Carbenoxolone induces permeability transition pore opening in rat mitochondria via the translocator protein TSPO and connexin43

Azarashvili

Baburina

Grachev

et al. 2014

Archives of Biochemistry and Biophysics

Self Cite

View full text Add to dashboard Cite

show abstract

“…The formation of the mitochondrial permeability transition pore (PTP) triggered by Ca 2+ overload or reactive oxygen is well documented [27][28][29][30]. This might happen by excitotoxicity including excessive glutamate release from depolarized neurons or dead cells, which causes permanent activation of glutamate receptors and persistent increase in the cytosolic Ca 2+ concentration [31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

Förster

Reiser

2015

Purinergic Signalling

Self Cite

View full text Add to dashboard Cite

This review describing the role of P2Y receptors in neuropathological conditions focuses on obvious differences between results demonstrating either a role in neuroprotection or in neurodegeneration, depending on in vitro and in vivo models. Such critical juxtaposition puts special emphasis on discussions of beneficial and detrimental effects of P2Y receptor agonists and antagonists in these models. The mechanisms reported to underlie the protection in vitro include increased expression of oxidoreductase genes, like carbonyl reductase and thioredoxin reductase; increased expression of inhibitor of apoptosis protein-2; extracellular signal-regulated kinase-and Akt-mediated antiapoptotic signaling; increased expression of Bcl-2 proteins, neurotrophins, neuropeptides, and growth factors; decreased Bax expression; non-amyloidogenic APP shedding; and increased neurite outgrowth in neuronal cells. Animal studies investigating the influence of P2Y receptors in middle cerebral artery occlusion (MCAO) models for stroke prove beneficial effects of P2Y receptor antagonists. In MCAO mice and rats, the application of broad-range P2 receptor antagonists decreased the infarct volume and improved neurological outcome. Moreover, antagonists of the P2Y 1 receptor, one of the most abundant P2Y receptor subtypes in brain tissue, decreased neuronal loss and improved spatial memory in rats after traumatic brain injury (TBI). Currently available data show a discrepancy between in vitro and in vivo models concerning the benefits of P2Y receptor activation in pathological conditions. In vitro models demonstrate protection by P2Y receptor agonists, but in vivo P2Y receptor activation deteriorates the outcome after MCAO and controlled cortical impact brain injury, a TBI model. To broaden the scope of the review, we additionally discuss publications that demonstrate detrimental effects of P2Y receptor agonists in vitro and publications showing protective effects of agonists in vivo. All these studies help to better understand the significant role of P2Y receptors especially in stroke models and to develop pharmacological strategies for the treatment of stroke.

show abstract

Bibliography

2014

Intracellular Calcium

View full text Add to dashboard Cite

Calcium-induced permeability transition in rat brain mitochondria is promoted by carbenoxolone through targeting connexin43

Abstract: Azarashvili T, Baburina Y, Grachev D, Krestinina O, Evtodienko Y, Stricker R, Reiser G. Calcium-induced permeability transition in rat brain mitochondria is promoted by carbenoxolone through targeting connexin43.

Cited by 46 publications

References 45 publications

Carbenoxolone induces permeability transition pore opening in rat mitochondria via the translocator protein TSPO and connexin43

Carbenoxolone induces permeability transition pore opening in rat mitochondria via the translocator protein TSPO and connexin43

Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

Bibliography

Contact Info

Product

Resources

About