<i>m</i>‐Iodobenzylguanidine increases the mitochondrial Ca<sup>2+</sup> pool in isolated hepatocytes

Juedes, Marlene J.; Kass, George E.N.; Orrenius, Sten

doi:10.1016/0014-5793(92)81179-p

Cited by 16 publications

(7 citation statements)

References 34 publications

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“…(24), with and without the potassium channel blocker, 5-hydroxydecanoate (5-HD; RBI) (25). In a separate series of experiments, COS-7 cells were pretreated (10 min) with thapsigargin, an inhibitor of the endoplasmic reticulum Ca 2ϩ -ATPase (26), ryanodine, which depletes endoplasmic Ca 2ϩ stores (27), and m-iodobenzylguanidine (MIBG, Sigma), an inhibitor of Ca 2ϩ release from mitochondria (28,29). All drugs except 5-HD were dissolved in dimethyl sulfoxide, which did not exceed 0.1% in its final concentration.…”

Section: Experimental Protocolmentioning

confidence: 99%

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Jovanović

et al. 1999

FASEB j.

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Metabolic injury is a complex process affecting various tissues, with intracellular Ca2+ loading recognized as a common precipitating event leading to cell death. We have recently observed that cells overexpressing recombinant ATP-sensitive K+ (KATP) channel subunits may acquire resistance against metabolic stress. To examine whether, under metabolic challenge, intracellular Ca2+ homeostasis can be maintained by an activator of channel proteins, we delivered Kir6.2 and SUR2A genes, which encode KATP channel subunits, into a somatic cell line lacking native KATP channels. Hypoxia-reoxygenation was simulated by application and removal of the mitochondrial poison 2,4 dinitrophenol. Under such metabolic stress, Ca2+ loading was induced by Ca2+ influx during hypoxia and release of Ca2+ from intracellular stores during reoxygenation. Delivery of Kir6.2/SUR2A genes, in conjunction with the KATP channel activator pinacidil, prevented intracellular Ca2+ loading irrespective of whether the channel opener was applied throughout the duration of hypoxia-reoxygenation or transiently during the hypoxic or reoxygenation stage. In all stages of injury, the effect of pinacidil was inhibited by the selective antagonist of KATP channel, 5-hydroxydecanoate. The present study provides evidence that combined use of gene delivery and pharmacological targeting of recombinant proteins can handle intracellular Ca2+ homeostasis under hypoxia-reoxygenation irrespective of the stage of the metabolic insult.

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Section: Experimental Protocolmentioning

confidence: 99%

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Jovanović

et al. 1999

FASEB j.

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“…Hydroperoxides and quinones which cause rapid and extensive oxidation of mitochondrial pyridine nucleotides have been observed to cause Ca 2+ release from rat liver mitochondria [17,20]. This efflux was accompanied by the hydrolysis of NAD + to release nicotinamide and could be prevented by added nicotinamide in one study [17] and by the more specific ADP-ribosylation inhibitor m-iodobenzylguanidine in the other [19,20]. In the context of the model proposed above, these suggest that the extensive increase in matrix NAD + concentrations promotes ADP-ribosylation of ANT and its conversion to the leaky C-conformation.…”

Section: A Covalently Modified Two-state Model Of the Adenine Nucleotmentioning

confidence: 99%

“…Here we reconsider this conclusion and demonstrate that the velocity of the ANT can be reduced by more than half by nicotinamide addition to isolated mitochondria: further, addition of T3 at 10 pM restored the rate to normal and this was abolished by concomitant addition of nicotinamide. We go on to propose a model based on alteration of the relative proportions of the two distinct conformations of the ANT (see [16]) by ADP-ribosylation which may offer a molecular mechanism not only for the transport effects of T~ but also for those of oxidative stress and ADP-ribosylation inhibitors on Ca 2+ [17][18][19][20], H + [21,22], and K + [22][23][24] transfer across the mitochondrial inner membrane.…”

Section: Introductionmentioning

confidence: 99%

Direct thyroid hormone signalling via ADP‐ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter

Mowbray

Hardy

1996

FEBS Letters

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Addition of triiodothyronine at 10 pM in vitro to hypothyroid rat liver mitochondria doubles the rate of the adenine nucleotide transporter at low ADP concentrations. Nicotinamide abolishes this effect in parallel with its inhibition of the ADP-ribosylation of an inner membrane protein identical in size to the transporter. Nieotinamide also renders euthyroid preparations indistinguishable from hypothyroid ones. A mechanism is offered to explain these findings in which it is proposed that the adenine nucleotide transporter is a true allosteric protein and that its covalent modification by ADP-ribosylation increases the stability of the less favoured externally-facing C-conformation and thus increases the proportion of transporters in this orientation: although the C-conformation is significantly more leaky to cations than the tight matrix-facing M-conformation, this enhances ADP import. This model is shown to offer an explanation not only for the transport effects of T3 but also for those of oxidative stress and ADP-ribosylation inhibitors on Ca 2+, H ÷ and K + transfer across the mitochondrial inner membrane. Ca 2+ at 30 nM appears to stabilize the Mconformation of the transporter by a mechanism other than ADP-ribosylation.

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“…(8,11,12). However, under a pathologic situation in which cells are exposed to high levels of Ca2+, mitochondria have been found to start sequestering significant amounts of Ca2+ (13,14). Mitochondria take up Ca2+ electrophoretically through a uniport transporter.…”

Section: C(2+ Transport Acrossmentioning

confidence: 99%

Calcium Signaling and Cytotoxicity

Kass¹,

Orrenius²

1999

Environmental Health Perspectives

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The divalent calcium cation Ca2+ is used as a major signaling molecule during cell signal transduction to regulate energy output, cellular metabolism, and phenotype. The basis to the signaling role of Ca2+ is an intricate network of cellular channels and transporters that allow a low resting concentration of Ca2+ in the cytosol of the cell (lCa2+1) but that are also coupled to major dynamic and rapidly exchanging stores. This enables extracellular signals from hormones and growth factors to be transduced as ICa2+li spikes that are amplitude and frequency encoded. There is considerable evidence that a number of toxic environmental chemicals target these Ca2+ signaling processes, alter them, and induce cell death by apoptosis. Two major pathways for apoptosis will be considered. The first one involves Ca2+-mediated expression of ligands that bind to and activate death receptors such as CD95 (Fas, APO-1). In the second pathway, Ca2+ has a direct toxic effect and its primary targets include the mitochondria and the endoplasmic reticulum (ER). Mitochondria may respond to an apoptotic Ca2+ signal by the selective release of cytochrome c or through enhanced production of reactive oxygen species and opening of an inner mitochondrial membrane pore. Toxic agents such as the environmental pollutant tributyltin or the natural plant product thapsigargin, which deplete the ER Ca2+ stores, will induce as a direct result of this effect the opening of plasma membrane Ca2+ channels and an ER stress response. In contrast, under some conditions, Ca2+ signals may be cytoprotective and antagonize the apoptotic machinery. -Environ Health Perspect 1 07(Suppl 1 ): 25-35 (1999). http://ehpnet1.niehs.nih.gov/docs/1999/Suppl-1/25-35kass/abstracthtml

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m‐Iodobenzylguanidine increases the mitochondrial Ca²⁺ pool in isolated hepatocytes

Cited by 16 publications

References 34 publications

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Direct thyroid hormone signalling via ADP‐ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter

Calcium Signaling and Cytotoxicity

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m‐Iodobenzylguanidine increases the mitochondrial Ca2+ pool in isolated hepatocytes

Cited by 16 publications

References 34 publications

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca2+homeostasis under metabolic stress

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca2+homeostasis under metabolic stress

Direct thyroid hormone signalling via ADP‐ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter

Calcium Signaling and Cytotoxicity

Contact Info

Product

Resources

About

m‐Iodobenzylguanidine increases the mitochondrial Ca²⁺ pool in isolated hepatocytes

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress