Voltage-gated calcium channel blockers deregulate macroautophagy in cardiomyocytes

Pushparaj, Charumathi; Das, Arindam; Purroy, Rosa; Nàger, Mireia; Herreros, Judit; Pamplona, Reinald; Cantı́, Carles

doi:10.1016/j.biocel.2015.09.010

Cited by 21 publications

(14 citation statements)

References 67 publications

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“…by ERS and subsequent Cyt-c release from mitochondria 48 . In addition to ERS, our study also found that Tchannel inhibitor intervention inhibited autophagy flux, which is consistent with previous research 31,33,49 . With ERS inhibitor analysis, we demonstrate ERS is an upstream signal and could be used as a therapeutic target for CACNA1H downregulation-induced muscular atrophy.…”

Section: Discussionsupporting

confidence: 93%

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

Hao

et al. 2020

Cell Death Dis

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Multiple vaginal delivery (MVD) is an important factor for pelvic floor muscle (PFM) function decline and pelvic floor dysfunction (PFD). PFD is common in middle-aged and elderly women, but its pathogenesis is not clear. In this study, we found that the expression of CACNA1H was lower in the PFM of old mice after MVD compared with old or adult mice. In in-vitro studies, we found that treatment with the T-type Ca 2+ channel (T-channel) inhibitor NNC-55 or downregulation of the CACNA1H gene by siRNA intervention promoted myotube atrophy and apoptosis. Mechanistically, we revealed that NNC-55 increased the expression of GRP78 and DDIT3 in myotubes, indicating endoplasmic reticulum stress (ERS) activation, and that the IRE1 and PERK pathways might be involved in this effect. NNC-55 induced the formation of autophagosomes but inhibited autophagy flux. Moreover, rapamycin, an autophagy activator, did not rescue myotube atrophy or apoptosis induced by NNC-55, and the autophagy inhibitors 3-MA and HCQ accelerated this damage. Further studies showed that the ERS inhibitors 4-PBA and TUDAC relieved NNC-55-induced damage and autophagy flux blockade. Finally, we found multisite muscle atrophy and decreased muscle function in Cacna1h −/− (TH-null) mice, as well as increased autophagy inhibition and apoptotic signals in the PFM of old WT mice after MVD and TH-null mice. Taken together, our results suggest that MVD-associated PFD is partially attributed to CACNA1H downregulation-induced PFM atrophy and that ERS is a potential therapeutic target for this disease.

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Section: Discussionsupporting

confidence: 93%

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

Hao

et al. 2020

Cell Death Dis

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“…A negligible participation of the calcium blockade on the TNFα production and antimicrobial responses induced by loperamide was observed in mycobacterium-infected macrophages, as the restoration of intracellular calcium levels by Bay K8644 did not prevent M. smegmatis killing. This phenomenon was unexpected, because calcium channel blockade triggers antimicrobial autophagy [35,36]. M. tuberculosis has been reported to interfere with macrophage microbicidal mechanisms and to inhibit murine and human macrophage Ca 2+ signaling to evade immune detection or decrease phagolysosome formation and macrophage reactive oxygen species production, contributing to the intracellular survival of M. tuberculosis [37].…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial and immunomodulatory activity induced by loperamide in mycobacterial infections

Juárez

Ruíz

Cortez

et al. 2018

International Immunopharmacology

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Loperamide is an antidiarrheal drug that targets μ-opioid receptors and calcium channels. A previous report demonstrated that loperamide induces autophagy and enhances antimicrobial activity towards M. tuberculosis in murine and human alveolar macrophages. The aim of this study was to evaluate the immunomodulatory effects of loperamide on macrophages with respect to cytokine and antimicrobial peptide production during mycobacterial infection. We infected monocyte-derived macrophages (macrophages) with M. tuberculosis H37Rv at a multiplicity of infection (MOI) of 5 and treated the cells with 3 μM loperamide. Cytokine production in the supernatants of 24-h cultures and gene expression of the cytokines TNFα, IL1β and IL10 and the antimicrobial peptides LL37 and bactericidal/permeability increasing protein (BPI) in the cell lysates was measured. Intracellular bacterial loads were evaluated by enumerating colony-forming units 3 days posttreatment for M. tuberculosis and 24 h posttreatment for M. smegmatis. We observed that loperamide exerted an immunomodulatory effect on TNFα production in human macrophages infected with M. tuberculosis and that these responses were independent of the bacteria, as they also occurred when macrophages were infected with M. smegmatis and to a lesser extent with M. bovis. In addition, antibacterial mechanisms triggered by loperamide induced a significant reduction in bacterial load and an upregulation of BPI and LL37 gene expression. Thus, our results show that loperamide exerts immunomodulatory effects, which supports its use for additional medical conditions other than diarrhea.

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“…Recently, it was demonstrated that L-type and T-type calcium channel blockers (nifedipine and mibefradil, respectively) differentially regulate autophagy in cardiomyocytes. 98 Specifically, nifedipine triggers the activation of autophagy, whereas mibefradil inhibits constitutive autophagy. The effect of mibefradil is mimicked by siRNA-mediated knockdown of T-type CACNA1H/Cav3.2 (calcium voltage-gated channel subunit alpha1 H) but not CACNA1G/Cav3.1 (calcium voltage-gated channel subunit alpha1 G) channels.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

“…In contrast, silencing of Ltype CACNA1C/Cav1.2 (calcium voltage-gated channel subunit alpha1 C) and CACNA1D/Cav1.3 (calcium voltage-gated channel subunit alpha1 D) channels results in accumulation of both LC3-II and SQSTM1/p62 (sequestosome 1), contrasting with the effect of nifedipine. 98 One of the possible explanation for this discrepancy is related to the fact that nifedipine (which is known for its L-type-channel specific action) is capable of blocking T-type channels as well. 99 Recently, the role of intracellular VGCC in autophagy has been revealed.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Ion channels in the regulation of autophagy

et al. 2017

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Autophagy is a cellular process in which the cell degrades and recycles its own constituents. Given the crucial role of autophagy in physiology, deregulation of autophagic machinery is associated with various diseases. Hence, a thorough understanding of autophagy regulatory mechanisms is crucially important for the elaboration of efficient treatments for different diseases. Recently, ion channels, mediating ion fluxes across cellular membranes, have emerged as important regulators of both basal and induced autophagy. However, the mechanisms by which specific ion channels regulate autophagy are still poorly understood, thus underscoring the need for further research in this field. Here we discuss the involvement of major types of ion channels in autophagy regulation.

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Voltage-gated calcium channel blockers deregulate macroautophagy in cardiomyocytes

Cited by 21 publications

References 67 publications

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

Antimicrobial and immunomodulatory activity induced by loperamide in mycobacterial infections

Ion channels in the regulation of autophagy

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