LOE 908: A Specific Blocker of Nonselective Cation Channel

Miwa, Soichi; Iwamuro, Yasushi; Zhang, Xiaofeng; Kawanabe, Yoshifumi; Masaki, Τοmoh

doi:10.1111/j.1527-3466.2000.tb00033.x

Cited by 5 publications

(5 citation statements)

References 37 publications

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“…of six different experiments (b), ns ¼ not significant. (1) SOCCs (Krautwurst et al, 1992;Miwa et al, 2000;Kawanabe et al, 2002). As indicated in Figure 4c and d, LOE 908 almost completely blocked the hyperforin-induced (10 mM) elevation of [Na þ ] i and [Ca 2 þ ] i in human platelets with IC 50 values around 5 mM.…”

Section: Hyperforin Activates Nonselective Cation Channelsmentioning

confidence: 67%

“…However, it is known that the actions of SK&F 96365 are nonspecific as it suppresses both NSCCs and store operated calcium channels (SOCCs) (Chung et al ., 1994; Franzius et al ., 1994; Koch et al ., 1994). To further confirm that hyperforin activates NSCCs, we also investigated the compound LOE 908, which inhibits two classes of NSCCs (NSCC1 and NSCC2) but has no effect on SOCCs (Krautwurst et al ., 1992; Miwa et al ., 2000; Kawanabe et al , 2002). As indicated in Figure 4c and d, LOE 908 almost completely blocked the hyperforin‐induced (10 μ M ) elevation of [Na + ] i and [Ca 2+ ] i in human platelets with IC 50 values around 5 μ M .…”

Section: Resultsmentioning

confidence: 99%

“…Pharmacologically, two subclasses have been identified by the parallel use of SK&F 96365 and LOE 908. SK&F 96365 only blocks NSCC2 channels but also to some extent SOCCs, while LOE 908 is specific for NSCCs but does not differentiate between the presumed subclasses NSCC1 and NSCC2 (Krautwurst et al ., 1992; Miwa et al ., 2000). Our findings with SK&F 96365 and LOE 908 (Figures 4; 5b,d and 6b,d) for both cell types suggest that the activation of NSCCs by hyperforin is possibly restricted to the NSCC2 subtype.…”

Section: Discussionmentioning

confidence: 99%

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Hyperforin activates nonselective cation channels (NSCCs)

Treiber

Singer

Henke

et al. 2005

British J Pharmacology

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1 A large body of evidence supports the preclinical antidepressant profile of hyperforin including inhibition of the synaptosomal uptake of several neurotransmitters by hyperforin and studies in behavioural models. In contrast to other antidepressants, hyperforin does not directly inhibit neurotransmitter transporters, but instead uptake inhibition seems to be the consequence of an elevated intracellular sodium concentration (

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Section: Hyperforin Activates Nonselective Cation Channelsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hyperforin activates nonselective cation channels (NSCCs)

Treiber

Singer

Henke

et al. 2005

British J Pharmacology

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“…Although apogossypol induced extensive ER membrane reorganization in Ca 2+ -free conditions, LOE-908, a broad spectrum cation channel inhibitor [34], completely blocked apogossypol-induced ER membrane reorganization in fission yeast (Figure 5A), which suggested a requirement of a cation influx other than Ca 2+ . A series of elimination experiments revealed that removal of extracellular Na + , but not K + , Mg 2+ or Ca 2+ , markedly decreased apogossypol-induced ER membrane reorganization (Figure 5A and data not shown).…”

Section: Resultsmentioning

confidence: 98%

Endoplasmic Reticulum Membrane Reorganization Is Regulated by Ionic Homeostasis

et al. 2013

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Recently we described a new, evolutionarily conserved cellular stress response characterized by a reversible reorganization of endoplasmic reticulum (ER) membranes that is distinct from canonical ER stress and the unfolded protein response (UPR). Apogossypol, a putative broad spectrum BCL-2 family antagonist, was the prototype compound used to induce this ER membrane reorganization. Following microarray analysis of cells treated with apogossypol, we used connectivity mapping to identify a wide range of structurally diverse chemicals from different pharmacological classes and established their ability to induce ER membrane reorganization. Such structural diversity suggests that the mechanisms initiating ER membrane reorganization are also diverse and a major objective of the present study was to identify potentially common features of these mechanisms. In order to explore this, we used hierarchical clustering of transcription profiles for a number of chemicals that induce membrane reorganization and discovered two distinct clusters. One cluster contained chemicals with known effects on Ca2+ homeostasis. Support for this was provided by the findings that ER membrane reorganization was induced by agents that either deplete ER Ca2+ (thapsigargin) or cause an alteration in cellular Ca2+ handling (calmodulin antagonists). Furthermore, overexpression of the ER luminal Ca2+ sensor, STIM1, also evoked ER membrane reorganization. Although perturbation of Ca2+ homeostasis was clearly one mechanism by which some agents induced ER membrane reorganization, influx of extracellular Na+ but not Ca2+ was required for ER membrane reorganization induced by apogossypol and the related BCL-2 family antagonist, TW37, in both human and yeast cells. Not only is this novel, non-canonical ER stress response evolutionary conserved but so also are aspects of the mechanism of formation of ER membrane aggregates. Thus perturbation of ionic homeostasis is important in the regulation of ER membrane reorganization.

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“…The capacitative influx route is also inhibited by some inhibitors of the P450 system (Montero et al 1992). Recently, another compound, LOE 908, has been shown to inhibit Ca 2 ‡ influx into myeloid cells (Krautwurst et al 1993) and a number of cell types with a pharmacology that suggests that it may also inhibit this non-specific Ca 2 ‡ channel (Miwa et al 2000).…”

Section: Ca 2 ‡ -Channel Opening and Ca 2 ‡ Influxmentioning

confidence: 99%

Ca2+, calpain and 3-phosphorylated phosphatidyl inositides; decision-making signals in neutrophils as potential targets for therapeutics

Tian

Dewitt

Laffafian

et al. 2004

Journal of Pharmacy and Pharmacology

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The chemical signals within neutrophils that control their behaviour are complex and these signals control the complex activity of neutrophils with precision. Failure of neutrophils to reform their antibacterial activity would lead to infection, while over-activity of neutrophils may lead to tissue damage and inflammatory disease. The identity of some of the intracellular signals is becoming clear and insights into the potential for interplay between them are being sought. Although it is well established that cytosolic free Ca 2 ‡ plays a role, it is only recently that the importance of intracellular protease, calpain, and the 3-position phosphorylated phosphatidyl inositides is becoming recognised. In this review these three key signals are discussed as potential therapeutic targets for the modulation of neutrophil activity.

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LOE 908: A Specific Blocker of Nonselective Cation Channel

Cited by 5 publications

References 37 publications

Hyperforin activates nonselective cation channels (NSCCs)

Hyperforin activates nonselective cation channels (NSCCs)

Endoplasmic Reticulum Membrane Reorganization Is Regulated by Ionic Homeostasis

Ca2+, calpain and 3-phosphorylated phosphatidyl inositides; decision-making signals in neutrophils as potential targets for therapeutics

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