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Pharmacological investigation of mitochondrial ca(2+) transport in central neurons: studies with CGP-37157, an inhibitor of the mitochondrial Na(+)-Ca(2+) exchanger.
Cell Calcium. 2000 Nov-Dec; 28(5-6):317-27.CC

Abstract

Mitochondria buffer large changes in [Ca(2+)](i)following an excitotoxic glutamate stimulus. Mitochondrial sequestration of [Ca(2+)](i)can beneficially stimulate oxidative metabolism and ATP production. However, Ca(2+)overload may have deleterious effects on mitochondrial function and cell survival, particularly Ca(2+)-dependent production of reactive oxygen species (ROS) by the mitochondria. We recently demonstrated that the mitochondrial Na(+)-Ca(2+)exchanger in neurons is selectively inhibited by CGP-37157, a benzothiazepine analogue of diltiazem. In the present series of experiments we investigated the effects of CGP-37157 on mitochondrial functions regulated by Ca(2+). Our data showed that 25 microM CGP-37157 quenches DCF fluorescence similar to 100 microM glutamate and this effect was enhanced when the two stimuli were applied together. CGP-37157 did not increase ROS generation and did not alter glutamate or 3mM hydrogen-peroxide-induced increases in ROS as measured by DHE fluorescence. CGP-37157 induces a slight decrease in intracellular pH, much less than that of glutamate. In addition, CGP-37157 does not enhance intracellular acidification induced by glutamate. Although it is possible that CGP-37157 can enhance mitochondrial respiration both by blocking Ca(2+)cycling and by elevating intramitochondrial Ca(2+), we did not observe any changes in ATP levels or toxicity either in the presence or absence of glutamate. Finally, mitochondrial Ca(2+)uptake during an excitotoxic glutamate stimulus was only slightly enhanced by inhibition of mitochondrial Ca(2+)efflux. Thus, although CGP-37157 alters mitochondrial Ca(2+)efflux in neurons, the inhibition of Na(+)-Ca(2+)exchange does not profoundly alter glutamate-mediated changes in mitochondrial function or mitochondrial Ca(2+)content.

Authors+Show Affiliations

Department of Pharmacology, University of Pittsburgh, School of Medicine, Pittsburgh, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11115371

Citation

Scanlon, J M., et al. "Pharmacological Investigation of Mitochondrial Ca(2+) Transport in Central Neurons: Studies With CGP-37157, an Inhibitor of the Mitochondrial Na(+)-Ca(2+) Exchanger." Cell Calcium, vol. 28, no. 5-6, 2000, pp. 317-27.
Scanlon JM, Brocard JB, Stout AK, et al. Pharmacological investigation of mitochondrial ca(2+) transport in central neurons: studies with CGP-37157, an inhibitor of the mitochondrial Na(+)-Ca(2+) exchanger. Cell Calcium. 2000;28(5-6):317-27.
Scanlon, J. M., Brocard, J. B., Stout, A. K., & Reynolds, I. J. (2000). Pharmacological investigation of mitochondrial ca(2+) transport in central neurons: studies with CGP-37157, an inhibitor of the mitochondrial Na(+)-Ca(2+) exchanger. Cell Calcium, 28(5-6), 317-27.
Scanlon JM, et al. Pharmacological Investigation of Mitochondrial Ca(2+) Transport in Central Neurons: Studies With CGP-37157, an Inhibitor of the Mitochondrial Na(+)-Ca(2+) Exchanger. Cell Calcium. 2000 Nov-Dec;28(5-6):317-27. PubMed PMID: 11115371.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological investigation of mitochondrial ca(2+) transport in central neurons: studies with CGP-37157, an inhibitor of the mitochondrial Na(+)-Ca(2+) exchanger. AU - Scanlon,J M, AU - Brocard,J B, AU - Stout,A K, AU - Reynolds,I J, PY - 2000/12/15/pubmed PY - 2001/3/3/medline PY - 2000/12/15/entrez SP - 317 EP - 27 JF - Cell calcium JO - Cell Calcium VL - 28 IS - 5-6 N2 - Mitochondria buffer large changes in [Ca(2+)](i)following an excitotoxic glutamate stimulus. Mitochondrial sequestration of [Ca(2+)](i)can beneficially stimulate oxidative metabolism and ATP production. However, Ca(2+)overload may have deleterious effects on mitochondrial function and cell survival, particularly Ca(2+)-dependent production of reactive oxygen species (ROS) by the mitochondria. We recently demonstrated that the mitochondrial Na(+)-Ca(2+)exchanger in neurons is selectively inhibited by CGP-37157, a benzothiazepine analogue of diltiazem. In the present series of experiments we investigated the effects of CGP-37157 on mitochondrial functions regulated by Ca(2+). Our data showed that 25 microM CGP-37157 quenches DCF fluorescence similar to 100 microM glutamate and this effect was enhanced when the two stimuli were applied together. CGP-37157 did not increase ROS generation and did not alter glutamate or 3mM hydrogen-peroxide-induced increases in ROS as measured by DHE fluorescence. CGP-37157 induces a slight decrease in intracellular pH, much less than that of glutamate. In addition, CGP-37157 does not enhance intracellular acidification induced by glutamate. Although it is possible that CGP-37157 can enhance mitochondrial respiration both by blocking Ca(2+)cycling and by elevating intramitochondrial Ca(2+), we did not observe any changes in ATP levels or toxicity either in the presence or absence of glutamate. Finally, mitochondrial Ca(2+)uptake during an excitotoxic glutamate stimulus was only slightly enhanced by inhibition of mitochondrial Ca(2+)efflux. Thus, although CGP-37157 alters mitochondrial Ca(2+)efflux in neurons, the inhibition of Na(+)-Ca(2+)exchange does not profoundly alter glutamate-mediated changes in mitochondrial function or mitochondrial Ca(2+)content. SN - 0143-4160 UR - https://www.unboundmedicine.com/medline/citation/11115371/Pharmacological_investigation_of_mitochondrial_ca_2+__transport_in_central_neurons:_studies_with_CGP_37157_an_inhibitor_of_the_mitochondrial_Na_+__Ca_2+__exchanger_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0143-4160(00)90171-4 DB - PRIME DP - Unbound Medicine ER -