Inhibition of Ca<sup>2+</sup> transport in mitochondria by selective blockade of membrane mucopolysaccharides by hexamine cobaltichloride

Tashmukhamedov, B.A.; Gagel’gans, A. I.; Mamatkulov, Kh.M.; Makhmudova, Etibor M.

doi:10.1016/0014-5793(72)80721-x

Cited by 35 publications

(6 citation statements)

References 7 publications

(5 reference statements)

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“…It was previously reported that HAC inhibits the mitochondrial calcium uniporter, which mediates Ca 2ϩ entry into the mitochondrial matrix in response to changes in the mitochondrial membrane potential (15,16). It was also reported that [Ca 2ϩ ] m , which rises in accordance with [Ca 2ϩ ] c upon glucose stimulation, is associated with glucose-induced insulin secretion (17).…”

Section: Effect Of Hac On the Glucose-induced Rise In Cytosolic And Mmentioning

confidence: 96%

“…3ϩ ) is a trivalent complex cation of Co(III) and amine that has been known and used as an inhibitor of the mitochondrial calcium uniporter (15,20) and a radiation-sensitizing agent (36). The importance of [Ca 2ϩ ] m in regulation of glucose-induced insulin secretion from pancreatic ␤ cells (18) prompted us to study the effect of HAC on the secretory pathway.…”

Section: Effect Of Hac On the Glucose-induced Rise In Cytosolic And Mmentioning

confidence: 99%

“…Thus, inhibitors of glucose metabolism (5) and Ca 2ϩ channel-blocking agents, such as verapamil (6), nifedipine (7), and divalent cations (8 -14), suppress glucose-induced insulin secretion. Moreover, recent studies showed that the intramitochondrial Ca 2ϩ concentration ([Ca 2ϩ ] m ) increases in accordance with the rise in [Ca 2ϩ ] c upon glucose stimulation via a calcium transporter on the inner mitochondrial membrane (calcium uniporter) (15,16) and that the increase in [Ca 2ϩ ] m is closely associated with glucose-induced insulin secretion (17,18).…”

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confidence: 99%

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Hexamminecobalt(III) Chloride Inhibits Glucose-induced Insulin Secretion at the Exocytotic Process

Tsubamoto¹,

Eto²,

Noda³

et al. 2001

Journal of Biological Chemistry

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Hexamminecobalt(III) (HAC) chloride was found to have a potent inhibitory effect on glucose-induced insulin secretion from pancreatic islets. HAC at 2 mM inhibited the secretion in response to 22.2 mM glucose by 90% in mouse islets. Perifusion experiments revealed that the first phase of insulin secretion was severely suppressed and that the second phase of secretion was completely abrogated. Removal of HAC from the perifusate immediately restored insulin secretion with a transient overshooting above the normal level. However, HAC failed to affect glucose-induced changes in D-[6-14 C]glucose oxidation, levels of reduced forms of NAD and NADP, mitochondrial membrane potential, ATP content, cytosolic calcium concentration, or calcium influx into mitochondria. Furthermore, HAC inhibited 50 mM potassium-stimulated insulin secretion by 77% and 10 M mastoparan-stimulated insulin secretion in the absence of extracellular Ca 2؉ by 80%. The results of a co-immunoprecipitation study of lysates from insulin-secreting ␤HC9 cells using anti-syntaxin and anti-vesicle-associated membrane protein antibodies for immunoprecipitation or Western blotting suggested that HAC inhibited disruption of the SNARE complex, which is normally observed upon glucose challenge. These results suggest that the inhibitory effect of HAC on glucose-induced insulin secretion is exerted at a site(s) distal to the elevation of cytosolic [Ca 2؉ ], possibly in the exocytotic machinery per se; and thus, HAC may serve as a useful tool for dissecting the molecular mechanism of insulin exocytotic processes.Glucose-induced insulin secretion from pancreatic ␤ cells is regulated by generation of ATP through glucose metabolism and an increase in the cytosolic calcium concentration ([Ca 2ϩ ] c ) 1 (1-4). The following cascade has been generally accepted as the glucose-induced insulin secretory pathway. When glucose is metabolized in the cytosol and mitochondria, ATP is generated to promote closure of ATP-sensitive potassium (K ATP ) channels, and this depolarizes the plasma membrane potential. To examine the involvement of [Ca 2ϩ ] m in glucose-induced insulin secretion from isolated islets, we tested the effects of ruthenium red and hexamminecobalt(III) (HAC), both of which have been reported to be inhibitors of the mitochondrial calcium uniporter (15, 18 -20), on the secretion. Ruthenium red was also reported to inhibit insulin secretion from permeabilized ␤ cells through inhibition of the calcium uniporter (18). We also observed that ruthenium red at 100 M severely suppressed glucose-induced insulin secretion in mouse islets. However, under these conditions, Ca 2ϩ influx through the plasma membrane was almost completely inhibited. These results indicated that ruthenium red was not a suitable agent to study the relationship of [Ca 2ϩ ] m to glucose-induced insulin secretion in intact cells, different from the case of permeabilized cells. In contrast, HAC at 2 mM suppressed glucose-induced insulin secretion to the same extent as 100 M ruthenium red...

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Section: Effect Of Hac On the Glucose-induced Rise In Cytosolic And Mmentioning

confidence: 96%

Section: Effect Of Hac On the Glucose-induced Rise In Cytosolic And Mmentioning

confidence: 99%

mentioning

confidence: 99%

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Hexamminecobalt(III) Chloride Inhibits Glucose-induced Insulin Secretion at the Exocytotic Process

Tsubamoto¹,

Eto²,

Noda³

et al. 2001

Journal of Biological Chemistry

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“…In this context, it has been noted that coordination complexes of the first-row transition metal cobalt can also possess MCU-inhibitory activity. [33,36,40] In contrast to Ru, Co is naturally present within biological systems and is significantly less expensive. Thus, despite the lower potency of these compounds, these advantages suggest that a continued exploration of Co 3 + compounds as MCU inhibitors is warranted.…”

Section: Introductionmentioning

confidence: 99%

“…In this context, it has been noted that coordination complexes of the first‐row transition metal cobalt can also possess MCU‐inhibitory activity [33,36,40] . In contrast to Ru, Co is naturally present within biological systems and is significantly less expensive.…”

Section: Introductionmentioning

confidence: 99%

Investigation of Cobalt(III) Cage Complexes as Inhibitors of the Mitochondrial Calcium Uniporter

Bigham

Wilson

2023

Eur J Inorg Chem

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The mitochondrial calcium uniporter (MCU) mediates uptake of calcium ions (Ca 2 + ) into the mitochondria, a process that is vital for maintaining normal cellular function. Inhibitors of the MCU, the most promising of which are dinuclear ruthenium coordination compounds, have found use as both therapeutic agents and tools for studying the importance of this ion channel. In this study, six Co 3 + cage compounds with sarcophagine-like ligands were assessed for their abilities to inhibit MCU-mediated mitochondrial Ca 2 + uptake. These complexes were synthesized and characterized according to literature procedures and then investigated in cellular systems for their MCU-inhibitory activities. Among these six compounds, [Co(sen)] 3 + (3, sen = 5-(4-amino-2-azabutyl)-5-methyl-3,7-diaza-1,9-nonanediamine) was identified to be a potent MCU inhibitor, with IC 50 values of inhibition of 160 and 180 nM in permeabilized HeLa and HEK293T cells, respectively. Furthermore, the cellular uptake of compound 3 was determined, revealing moderate accumulation in cells. Most notably, 3 was demonstrated to operate in intact cells as an MCU inhibitor. Collectively, this work presents the viability of using cobalt coordination complexes as MCU inhibitors, providing a new direction for researchers to investigate.

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Binding Proteins and Membrane Transport

Carafoli

Crompton

1976

The Enzymes of Biological Membranes

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Inhibition of Ca²⁺ transport in mitochondria by selective blockade of membrane mucopolysaccharides by hexamine cobaltichloride

Cited by 35 publications

References 7 publications

Hexamminecobalt(III) Chloride Inhibits Glucose-induced Insulin Secretion at the Exocytotic Process

Hexamminecobalt(III) Chloride Inhibits Glucose-induced Insulin Secretion at the Exocytotic Process

Investigation of Cobalt(III) Cage Complexes as Inhibitors of the Mitochondrial Calcium Uniporter

Binding Proteins and Membrane Transport

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Inhibition of Ca2+ transport in mitochondria by selective blockade of membrane mucopolysaccharides by hexamine cobaltichloride

Cited by 35 publications

References 7 publications

Hexamminecobalt(III) Chloride Inhibits Glucose-induced Insulin Secretion at the Exocytotic Process

Hexamminecobalt(III) Chloride Inhibits Glucose-induced Insulin Secretion at the Exocytotic Process

Investigation of Cobalt(III) Cage Complexes as Inhibitors of the Mitochondrial Calcium Uniporter

Binding Proteins and Membrane Transport

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Inhibition of Ca²⁺ transport in mitochondria by selective blockade of membrane mucopolysaccharides by hexamine cobaltichloride