KB-R7943 Inhibits the Mitochondrial Ca&lt;sup&gt;2+&lt;/sup&gt; Uniporter but Not Na&lt;sup&gt;+&lt;/sup&gt;–Ca&lt;sup&gt;2+&lt;/sup&gt; Exchanger in Cardiomyocyte-Derived H9c2 Cells

Namekata, Iyuki; Odaka, Ryosuke; Hamaguchi, Satoshi; Tanaka, Hikaru

doi:10.1248/bpb.b20-00747

Cited by 6 publications

(4 citation statements)

References 18 publications

(26 reference statements)

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“…A further inhibitor, KB-R7943, may be taken into consideration, since it has recently been shown to alleviate P. aeruginosa –triggered inflammatory responses in vivo [ 97 ], and it may have a similar anti-inflammatory effect in the tumor micro-environment, therefore negatively affecting tumor growth. However, this drug is also a potent inhibitor of the plasma membrane (PM) Na + /Ca 2+ exchanger NCX1 [ 98 ] ( contra [ 99 ]) and its tumor-reducing action observed in a murine prostate xenograft model has been ascribed to its effect on the PM exchanger [ 100 ] rather than to inhibition of the mitochondrial channel.…”

Section: Mitochondrial Ion Channels and Their Pharmacological Targeting By Small Moleculesmentioning

confidence: 99%

Targeting mitochondrial ion channels for cancer therapy

2021

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Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.

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Section: Mitochondrial Ion Channels and Their Pharmacological Targeting By Small Moleculesmentioning

confidence: 99%

Targeting mitochondrial ion channels for cancer therapy

2021

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“…Thus, the concentration of KB‐R7943 used in the present study, 20 μM, can effectively block the reverse mode of the NCX without effecting above mentioned proteins in both neurons and astrocytes. It is still controversial whether KB‐R7943 inhibits the mitochondrial Ca 2+ uptake (Brustovetsky et al, 2011; Namekata et al, 2020; Santo‐Domingo et al, 2007; Storozhevykh et al, 2010; Wiczer et al, 2014) in cultured neurons and other cell types. Although during our experiments, we have not observed any abnormal Ca 2+ activity in jRGECO1a expressing neurons, to rule out the possible off‐target of KB‐R7943 on mitochondria, further assessment of neuronal and astrocytic mitochondrial function shall be considered, for instance, using mitochondria tagged GECIs in neurons and astrocytes to access the functionality during the Scc stimulation with the presence of KB‐R7943.…”

Section: Discussionmentioning

confidence: 99%

Increased membrane Ca²⁺ permeability drives astrocytic Ca²⁺ dynamics during neuronal stimulation at excitatory synapses

Hjukse,

Puebla,

Vindedal

et al. 2023

Glia

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Astrocytes are intricately involved in the activity of neural circuits; however, their basic physiology of interacting with nearby neurons is not well established. Using two‐photon imaging of neurons and astrocytes during higher frequency stimulation of hippocampal CA3‐CA1 Schaffer collateral (Scc) excitatory synapses, we could show that increasing levels of released glutamate accelerated local astrocytic Ca2+ elevation. However, blockage of glutamate transporters did not abolish this astrocytic Ca2+ response, suggesting that astrocytic Ca2+ elevation is indirectly associated with an uptake of extracellular glutamate. However, during the astrocytic glutamate uptake, the Na+/Ca2+ exchanger (NCX) reverse mode was activated, and mediated extracellular Ca2+ entry, thereby triggering the internal release of Ca2+. In addition, extracellular Ca2+ entry via membrane P2X receptors further facilitated astrocytic Ca2+ elevation via ATP binding. These findings suggest a novel mechanism of activity induced Ca2+ permeability increases of astrocytic membranes, which drives astrocytic responses during neuronal stimulation of CA3‐CA1 Scc excitatory synapses.

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“…Even though several NCX blockers (KB-R7943, SEA0400, SN-6, and YM-244769) are currently available [82,83], it is quite clear that besides NCX, these compounds also can interact with other membrane proteins [84][85][86]. Another fundamental obstacle is that the selective pharmacological targeting of tissue-specific NCX variants remains unavailable due to an incomplete understanding of the underlying molecular and cellular mechanisms [1,5,7,[9][10][11]60].…”

Section: Discussionmentioning

confidence: 99%

19F-NMR Probing of Ion-Induced Conformational Changes in Detergent-Solubilized and Nanodisc-Reconstituted NCX_Mj

Nguyen,

Strauss,

Refaeli

et al. 2024

IJMS

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Consecutive interactions of 3Na+ or 1Ca2+ with the Na+/Ca2+ exchanger (NCX) result in an alternative exposure (access) of the cytosolic and extracellular vestibules to opposite sides of the membrane, where ion-induced transitions between the outward-facing (OF) and inward-facing (IF) conformational states drive a transport cycle. Here, we investigate sub-state populations of apo and ion-bound species in the OF and IF states by analyzing detergent-solubilized and nanodisc-reconstituted preparations of NCX_Mj with 19F-NMR. The 19F probe was covalently attached to the cysteine residues at entry locations of the cytosolic and extracellular vestibules. Multiple sub-states of apo and ion-bound species were observed in nanodisc-reconstituted (but not in detergent-solubilized) NCX_Mj, meaning that the lipid-membrane environment preconditions multiple sub-state populations toward the OF/IF swapping. Most importantly, ion-induced sub-state redistributions occur within each major (OF or IF) state, where sub-state interconversions may precondition the OF/IF swapping. In contrast with large changes in population redistributions, the sum of sub-state populations within each inherent state (OF or IF) remains nearly unchanged upon ion addition. The present findings allow the further elucidation of structure–dynamic modules underlying ion-induced conformational changes that determine a functional asymmetry of ion access/translocation at opposite sides of the membrane and ion transport rates concurring physiological demands.

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KB-R7943 Inhibits the Mitochondrial Ca<sup>2+</sup> Uniporter but Not Na<sup>+</sup>–Ca<sup>2+</sup> Exchanger in Cardiomyocyte-Derived H9c2 Cells

Cited by 6 publications

References 18 publications

Targeting mitochondrial ion channels for cancer therapy

Targeting mitochondrial ion channels for cancer therapy

Increased membrane Ca²⁺ permeability drives astrocytic Ca²⁺ dynamics during neuronal stimulation at excitatory synapses

19F-NMR Probing of Ion-Induced Conformational Changes in Detergent-Solubilized and Nanodisc-Reconstituted NCX_Mj

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KB-R7943 Inhibits the Mitochondrial Ca<sup>2+</sup> Uniporter but Not Na<sup>+</sup>–Ca<sup>2+</sup> Exchanger in Cardiomyocyte-Derived H9c2 Cells

Cited by 6 publications

References 18 publications

Targeting mitochondrial ion channels for cancer therapy

Targeting mitochondrial ion channels for cancer therapy

Increased membrane Ca2+ permeability drives astrocytic Ca2+ dynamics during neuronal stimulation at excitatory synapses

19F-NMR Probing of Ion-Induced Conformational Changes in Detergent-Solubilized and Nanodisc-Reconstituted NCX_Mj

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Increased membrane Ca²⁺ permeability drives astrocytic Ca²⁺ dynamics during neuronal stimulation at excitatory synapses