The effects of phenothiazines and other calmodulin antagonists on the sarcoplasmic and endoplasmic reticulum Ca2+ pumps

Khan, Shahla Zafar; Longland, Clare L.; Michelangeli, Francesco

doi:10.1016/s0006-2952(00)00505-0

Cited by 42 publications

(27 citation statements)

References 44 publications

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“…Consistently with that finding, TAM and AMD induce the activation of a calcineurin-dependent reporter construct and cause the nuclear localization of Crz1p, a calcineurin-regulated transcription factor (34,51). These observations are consistent with TAM and AMD causing an increase in intracellular calcium, effects previously described for mammalian cells (14). Meund and Rao have extensively studied the mechanism by which AMD exerts antifungal activity and found that it induces increased calcium spikes in yeast cells (26).…”

Section: Discussionsupporting

confidence: 84%

“…Consistently with these observations, TAM activates a calcineurin-dependent reporter and triggers the nuclear localization of the calcineurin-dependent transcription factor Crz1p (34). These findings suggest that TAM induces an increase in intracellular calcium, a non-estrogen receptor-dependent effect previously described in mammalian cells (14). Based on these studies, it may be the case that the antifungal activity of TAM is the result of its effects on multiple physiologic processes in yeast.…”

supporting

confidence: 84%

“…To do so, we carried out an in vitro binding experiment using calmodulin-Sepharose beads and lysates of a S. cerevisiae strain harboring a GFP-tagged allele of MYO2, an essential calmodulin binding protein involved in a variety of cellular processes related to polarized growth (6,52). Total cell lysates from MYO2-GFP cells were treated with calmodulin beads in the presence of DMSO carrier, TAM (50 g/ml), or the known calmodulin inhibitor prochlorperazine (50 g/ml) (14). The immunoprecipitates were analyzed by Western blotting using anti-GFP antibody.…”

Section: Tam Interferes With Binding Of Myo2p To Calmodulin In Vitromentioning

confidence: 99%

“…Although the mechanisms of the estrogen receptor-independent effects of TAM remain a subject of debate (9), it is clear from a large body of literature that TAM has a wide range of effects on mammalian cell physiology, including antioxidant activity (47,48), antiangiogenesis properties (43), the stimulation of transforming growth factor beta secretion (28), the induction of intracellular calcium release (14), the alteration of cellular membrane properties (47), and the induction of apoptosis (2). Consistent with this plethora of cellular effects, TAM has been shown to target a number of proteins in mammalian cells, including calmodulin, protein kinase C, phospholipase C, phosphoinositide kinase, P-glycoprotein, and swell-induced chloride channels (9).…”

mentioning

confidence: 99%

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Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization

Dolan

Montgomery²,

Buchheit³

et al. 2009

Antimicrob Agents Chemother

106

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Tamoxifen (TAM), an estrogen receptor antagonist used primarily to treat breast cancer, has well-recognized antifungal properties, but the activity of TAM has not been fully characterized using standardized (i.e., CLSI) in vitro susceptibility testing, nor has it been demonstrated in an in vivo model of fungal infection. In addition, its mechanism of action remains to be clearly defined at the molecular level. Here, we report that TAM displays in vitro activity (MIC, 8 to 64 g/ml) against pathogenic yeasts (Candida albicans, other Candida spp., and Cryptococcus neoformans). In vivo, 200 mg/kg of body weight per day TAM reduced kidney fungal burden (؊1.5 log 10 CFU per g tissue; P ‫؍‬ 0.008) in a murine model of disseminated candidiasis. TAM is a known inhibitor of mammalian calmodulin, and TAM-treated yeast show phenotypes consistent with decreased calmodulin function, including lysis, decreased new bud formation, disrupted actin polarization, and decreased germ tube formation. The overexpression of calmodulin suppresses TAM toxicity, hypofunctional calmodulin mutants are hypersensitive to TAM, and TAM interferes with the interaction between Myo2p and calmodulin, suggesting that TAM targets calmodulin as part of its mechanism of action. Taken together, these experiments indicate that the further study of compounds related to TAM as antifungal agents is warranted.

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Section: Discussionsupporting

confidence: 84%

supporting

confidence: 84%

Section: Tam Interferes With Binding Of Myo2p To Calmodulin In Vitromentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization

Dolan

Montgomery²,

Buchheit³

et al. 2009

Antimicrob Agents Chemother

106

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“…To determine whether CaM plays a role in CDF and CDI induced by the increase of [Ca 2+ ] i , we investigated the effects of CPZ, a CaM inhibitor [25]. After the myocytes were pretreated with CPZ for at least 30 min, Ca 2+ -channel activity was recorded with the same protocol as mentioned above.…”

Section: Effects Of Cam Inhibitors On Cdf and CDImentioning

confidence: 99%

Distinct Roles of CaM and Ca2+/CaM-Dependent Protein Kinase II in Ca2+-Dependent Facilitation and Inactivation of Cardiac L-Type Ca2+ Channels

Nie

Liang

et al. 2007

J. Physiol. Sci

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L-type Ca 2+ channels have two opposing forms of autoregulatory feedback, Ca 2+ -dependent facilitation (CDF) and Ca 2+ -dependent inactivation (CDI), in response to increases in intracellular Ca 2+ concentration. Calmodulin (CaM) has been reported to mediate the two feedbacks. Although both the direct binding of CaM and the phosphorylation mediated by Ca 2+ /CaMdependent protein kinase II (CaMKII) have been suggested as underlying mechanisms, the detailed features remain to be clarified. In this study, we investigated the effects of CaM and CaMKII inhibitors on CDF and CDI with patch clamp cell-attached recordings in guinea-pig ventricular myocytes. We confirmed that a high-K + and high-Ca 2+ could induce an increase of the intracellular Ca 2+ concentration and subsequent CDF and CDI. We then found that CDF and CDI were both depressed and were finally abolished by treatment with a CaM inhibitor chlorpromazine (1-100 µM) in a concentration-dependent manner. Another CaM antagonist calmidazolium (1 µM) showed a similar effect. In contrast, CaMKII inhibitors, KN-62 (0.1-3 µM) and autocamtide 2-related inhibitory peptide (1 µM), delayed the development of CDF and CDI significantly, but they did not depress either CDF or CDI. These results imply that CaM is necessary and possiblly sufficient for the two mechanisms. We propose a hypothesis that CaM is a key molecule to bifurcate the Ca 2+ signal to CDF and CDI and that CaMKII plays a modulatory role in them both.

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Calcium Signalling in the Endothelium

Tran

Watanabe

The Vascular Endothelium I

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The effects of phenothiazines and other calmodulin antagonists on the sarcoplasmic and endoplasmic reticulum Ca2+ pumps

Cited by 42 publications

References 44 publications

Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization

Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization

Distinct Roles of CaM and Ca2+/CaM-Dependent Protein Kinase II in Ca2+-Dependent Facilitation and Inactivation of Cardiac L-Type Ca2+ Channels

Calcium Signalling in the Endothelium

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