The release of calcium from heart mitochondria by sodium

Carafoli, Ernesto; Tiozzo, Roberta; Lugli, Giovanni; Crovetti, F.; Kratzing, C. C.

doi:10.1016/0022-2828(74)90077-7

Cited by 342 publications

(124 citation statements)

References 18 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…30 Existence of a Na + /Ca 2+ exchange in mitochondria was first reported by Carafoli. 31 The further discovery of the benzothiazepine derivative CGP37157 as a mNCX blocker constituted a breakthrough for the functional characterization of the mNCX 32 ( Figure 1). However, CGP37157 is not only a mNCX blocker, at submicromolar concentrations, 33 but also it has been described as blocker of both VDCCs 34 and plasmalemal NCX, at micromolar concentrations, 35 as well.…”

Section: + Concentrations ([Camentioning

confidence: 99%

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

González‐Lafuente

Egea

León

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Benzothiazepine CGP37157 is widely used as tool to explore the role of mitochondria in cell Ca 2+ handling, by its blocking effect of the mitochondria Na + /Ca 2+ exchanger. Recently, CGP37157 has shown to exhibit neuroprotective properties. In the trend to improve its neuroprotection profile, we have synthesized ITH12505, an isosteric analogue having a methyl instead of chlorine at C2′ of the phenyl ring. ITH12505 has exerted neuroprotective properties similar to CGP37157 in chromaffin cells and hippocampal slices stressed with veratridine. Also, both compounds afforded neuroprotection in hippocampal slices stressed with glutamate. However, while ITH12505 elicited protection in SH-SY5Y cells stressed with oligomycin A/rotenone, CGP37157 was ineffective. In hippocampal slices subjected to oxygen/glucose deprivation plus reoxygenation, ITH12505 offered protection at 3−30 μM, while CGP37157 only protected at 30 μM. Both compounds caused blockade of Ca 2+ channels in high K + -depolarized SH-SY5Y cells. An in vitro experiment for assaying central nervous system penetration (PAMPA-BBB; parallel artificial membrane permeability assay for blood-brain barrier) revealed that both compounds could cross the blood−brain barrier, thus reaching their biological targets in the central nervous system. In conclusion, by causing a mild isosteric replacement in the benzothiazepine CGP37157, we have obtained ITH12505, with improved neuroprotective properties. These findings may inspire the design and synthesis of new benzothiazepines targeting mitochondrial Na + /Ca 2+ exchanger and L-type voltage-dependent Ca 2+ channels, having antioxidant properties.

show abstract

Section: + Concentrations ([Camentioning

confidence: 99%

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

González‐Lafuente

Egea

León

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…However, the influence of Li+ or C1 on Ca2+ release cannot be excluded because a small amount of Ca2+ was released by LiCI. This differs from cardiac muscle mitochondria, where the influence of Na+ could largely be duplicated by Li+ (14). Similar specificities for monovalent cations were observed in cardiac sarcolemmal vesicle Na+ : Ca2+ exchange and sarcolemmal membrane vesicle of mesenteric artery, i.e., Li+ could not be substituted for Na+ (28,29).…”

Section: Discussionmentioning

confidence: 78%

“…Na+-dependent Ca2+ release in cardiac muscle mitochondria is inhibited by calcium channel antagonists, diltiazem being much more effective than other classes of antagonists (3,4,15). In heart cells many of the effects of Na+-initiated Ca2+ release from mitochondria could to a certain degree be duplicated by lithium (Lit) (14). In this study we addressed a number of questions: Do mitochondria from VSM, as in the case of cardiac mitochondria, show Na+-dependent Ca2+ release?…”

Section: Introductionmentioning

confidence: 99%

Sodium-Dependent Calcium Release from Vascular Smooth Muscle Mitochondria.

2000

View full text Add to dashboard Cite

Interest in mitochondrial calcium (Ca2+) uptake and release waned as it became apparent that sarcoplasmic reticulum calcium stores dominate the control of cytoplasmic calcium concentration.Our recent demonstration of a very large rise in vascular smooth muscle (VSM) cytoplasmic sodium (Na+) concentration after inhibition of the sodium, potassium-ATPase (sodium pump) led us to several questions. Do VSM mitochondria show Na+-dependent Ca2+ release? Are the documented changes in cytoplasmic Na+ concentration sufficient to cause Ca2+ release? Do features of the cardiac mitochondrial exchange system, including differential sensitivity to a number of calcium antagonists and cation specificity, apply to VSM?We isolated mitochondria from bovine aorta and mesenteric arteries and employed arsenazo III as the Ca2+ indicator. Mitochondria from arterial vessels accumulated added calcium (up to 50 nmol Ca2+/mg protein) and released Ca2+ on exposure to Na+. This concentration-dependent relationship was linear from 0 to 10 mM of Nat, and it plateaued between 20 mM and 40 mM of Nat. VSM mitochondria exposed to 20 mM Na+ released 118±25 nmol Ca2+ per mg mitochondrial protein in 20 min, when a new equilibrium was reached. Lithium (Li+), in contrast to Na+, produced much smaller amounts of Ca2+ release from the VSM mitochondria. Na+-dependent Ca2+ release was antagonized in a concentration-dependent manner by diltiazem (0-320 pM) with a Ki of 10.2 hM. Nifedipine had a lesser effect, and verapamil produced almost no inhibition. VSM mitochondria responses resemble those from heart mitochondria in that Na+-dependent Ca2+ release is present with a similar range of sensitivity to Na+ and a similar pattern of influence of diltiazem, nifedipine and verapamil. However, the influence of Li+ on Ca2+ release was much smaller and the amount of the Ca2+ released was much greater for VSM mitochondria compared with that reported for heart mitochondria. The large amount of Ca2+ released and the range of Na+ concentration that provoked Ca2+ release being within the physiologically achievable range raise the interesting possibility that these mechanisms may modify intramitochondrial cytosolic Ca2+ concentration, and hence could potentially contribute to the contractile response that follows inhibition of the sodium pump. (Hypertens Res 2000; 23: 39-45)

show abstract

“…This is the permeability transition pore (PTP) [17], which opens as the concentration of Ca 2þ in the matrix exceeds a threshold. Mitochondria, however, also release Ca 2þ through exchangers, especially a Na þ /Ca 2þ exchanger (NCX) [18]. The operation of the ER/SR channels creates spatially restricted microdomains of high Ca 2þ concentration, which are necessary, for instance, for the contraction process in skeletal muscles and in cardiac cells [19,20].…”

Section: Control Of Calcium By Membrane Transportersmentioning

confidence: 99%

Calcium and signal transduction

Fedrizzi

Lim

Carafoli

2008

Biochem Molecular Bio Educ

View full text Add to dashboard Cite

Cell signaling is an essential process in which a variety of external signals, defined as first messengers, are translated inside the cells into specific responses, which are mediated by a less numerous group of second messengers. The exchange of signals became a necessity when the transition from monocellular to pluricellular life brought with it the division of labor among the cells of the organisms: unicellular organisms do not depend on the mutual exchange of signals, as they essentially only compete with each other for nutrients. Calcium (Ca2+) was selected during evolution as second messenger, because its chemistry made it a much more flexible ligand than the other abundant cations in the primordial environment (Na+, K+, Mg2+). Ca2+ can accept binding sites of irregular geometries and is thus ideally suited to be a carrier of biological information. The Ca2+ signal has properties that set it apart from those of all other biological messengers: they will be reviewed in this contribution. Among them, the ambivalent character of the Ca2+ signal is the most important: while essential to the viability of the cells, it can also easily become a conveyor of doom.

show abstract

The release of calcium from heart mitochondria by sodium

Cited by 342 publications

References 18 publications

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

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

Sodium-Dependent Calcium Release from Vascular Smooth Muscle Mitochondria.

Calcium and signal transduction

Contact Info

Product

Resources

About