M3 Muscarinic Receptor Signaling Stabilizes a Novel Mutant Human Ether-a-Go-Go-Related Gene Channel Protein via Phosphorylation of Heat Shock Factor 1 in Transfected Cells

Mahati, Endang; Li, Peili; Kurata, Yasutaka; Maharani, Nani; Ikeda, Naho; Sakata, Shinji; Ogura, Kazuyoshi; Miake, Junichiro; Aiba, Takeshi; Shimizu, Wataru; Nakasone, Naoe; Ninomiya, Haruaki; Higaki, Kazutaka; Yamamoto, Kazuhide; Nakai, Asami; Shirayoshi, Yasuaki; Hisatome, Ichiro

doi:10.1253/circj.cj-16-0712

Cited by 6 publications

(6 citation statements)

References 26 publications

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“…The results of this study showed a significant increase of Hsp60, Hsp70, and Hsp90 protein levels and of the HSF1‐Ser326 phosphorylation in the rat hippocampus following mAChRs stimulation. As already stated in the introduction, using mAChR agonist carbachol treatment in HEK293 cell line, it was found increased levels of HSF1 phosphorylation, mediated by PKC, and enhanced expression of Hsp70 and Hsp90 (Mahati et al, ). However, the present work have revealed, using in vivo rat model, novel data of acute or chronic mAChR activation on Hsps and HSF1 regulation in the rat hippocampus.…”

Section: Discussionmentioning

confidence: 81%

“…Hsp70 and Hsp90 (Mahati et al, 2016). However, the present work have revealed, using in vivo rat model, novel data of acute or chronic mAChR activation on Hsps and HSF1 regulation in the rat hippocampus.…”

mentioning

confidence: 66%

“…Previously, we showed that M 1 R are involved in FGFR1 transactivation in Oxo treatment‐induced neuronal axonal growth (Di Liberto, Borroto‐Escuela, et al, ). Recently, it has been shown that M 3 R activation leads to enhancement of Hsp70 and Hsp90 expression and phosphorylation of HSF1 (Mahati et al, ). In the present study, we evaluated the specificity of mAChR effects, using pretreatment with mAChR antagonist scopolamine, and we found a complete block of Oxo effects on Hsp60 and Hsp70 and even a reduction of the Hsp90 levels.…”

Section: Discussionmentioning

confidence: 99%

“…Concerning the Hsp regulation by mAChR activation very few data at present are available and recently one of them showed in HEK293 cell line that activation of PKC by carbachol augments phosphorylation of heat shock factor 1 (HSF1) and enhances expression of Hsp70 and Hsp90 (Mahati et al, 2016). In other experimental model, it has been showed that treatment with pilocarpine-induced status epilepticus increases Hsp25, Hsp32, and Hsp70 (Lively & Brown, 2011).…”

Section: Hsp Regulation By Machr Activationmentioning

confidence: 99%

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Heat shock protein (Hsp) regulation by muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus

Frinchi

Scaduto

Cappello

et al. 2018

Journal Cellular Physiology

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The cholinergic system plays a crucial role in modulating in the central nervous system physiological responses such as neurogenesis, neuronal differentiation, synaptic plasticity, and neuroprotection. In a recent study, we showed that Oxotremorine-M, a non-selective muscarinic acetylcholine receptor agonist, is able to transactivate the fibroblast growth factor receptor and to produce a significant increase in the hippocampal primary neurite outgrowth. In the present study we aimed to explore in the rat hippocampus the possible effect of acute or chronic treatment with Oxotremorine-M on some heat shock proteins (Hsp60, Hsp70, Hsp90) and on activation of related transcription factor heat shock factor 1 (HSF1). Following single injection of Oxotremorine-M (0.4 mg/kg) all Hsps examined were significantly increased in at least one of the time points studied (24, 48, and 72 hr). Treatment with Oxotremorine-M significantly increased the level of phosphorylated HSF1 in all time points studied, without change of protein levels. Similar pattern of Hsps changes was obtained following chronic Oxotremorine-M treatment (0.2 mg/kg) for 5 days. Surprisingly, following chronic treatment for 10 days no changes were observed in Hsps. The muscarinic acetylcholine receptor antagonist scopolamine (1 mg/kg) was able to completely block Oxotremorine-M effects on Hsps. In conclusion, considering the function of Hsps in protecting neuronal cells from deleterious proteotoxic stress, for example, protein mis-folding and aggregation, the results obtained indicate that muscarinic acetylcholine receptor activation may have implications in potential treatment of neurodegenerative disorders linked to protein aggregation, such as Alzheimer disease.

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Hsp Regulation By Machr Activationmentioning

confidence: 99%

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Heat shock protein (Hsp) regulation by muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus

Frinchi

Scaduto

Cappello

et al. 2018

Journal Cellular Physiology

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“…Nonetheless, there are some similarities in hERG/I Kr responses to PKC activation induced by PMA and a1-AR or M3 receptor stimulation. For example, acute agonism of a1-AR or M3 receptors inhibits hERG current and positively shifts V 1/2 in a manner that involves the N terminus of hERG (Thomas et al, 2004b;Cockerill et al, 2007;Liu et al, 2017), whereas chronic activation of a1-AR or M3 receptors increases hERG expression and current (Chen et al, 2010;Wang et al, 2014;Mahati et al, 2016). On the other hand, angiotensin II-mediated PKC Fig.…”

Section: Pkc-mediated Herg Regulationmentioning

confidence: 99%

Differential Regulation of Human Ether-à-Go-Go–Related Gene (hERG) Current and Expression by Activation of Protein Kinase C

et al. 2019

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The human ether-à-go-go-related gene (hERG) encodes the channel that conducts the rapidly activating delayed rectifier potassium current (I Kr) in the heart. Reduction in I Kr causes long QT syndrome, which can lead to fatal arrhythmias triggered by stress. One potential link between stress and hERG function is protein kinase C (PKC) activation; however, seemingly conflicting results regarding PKC regulation of hERG have been reported. We investigated the effects of PKC activation using phorbol 12-myristate 13-acetate (PMA) on hERG channels expressed in human embryonic kidney cell line 293 (HEK293) cells and I Kr in isolated neonatal rat ventricular myocytes. Acute activation of PKC by PMA (30 nM, 30 minutes) reduced both hERG current (I hERG) and I Kr. Chronic activation of PKC by PMA (30 nM, 16 hours) increased I Kr in cardiomyocytes and the expression level of hERG proteins; however, chronic (30 nM, 16 hours) PMA treatment decreased I hERG , which became larger than untreated control I hERG after PMA removal for 4 hours. Deletion of amino acid residues 2-354 (D2-354 hERG) or 1-136 of the N terminus (DN 136 hERG) abolished acute PMA (30 nM, 30 minutes)-mediated I hERG reduction. In contrast to wild-type hERG channels, chronic activation of PKC by PMA (30 nM, 16 hours) increased both D2-354 hERG and DN136 hERG expression levels and currents. The increase in hERG protein was associated with PKC-induced phosphorylation (inhibition) of Nedd4-2, an E3 ubiquitin ligase that mediates hERG degradation. We conclude that PKC regulates hERG in a balanced manner, increasing expression through inhibiting Nedd4-2 while decreasing current through targeting a site(s) within the N terminus.

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Regulation of cardiac ion channels by transcription factors: Looking for new opportunities of druggable targets for the treatment of arrhythmias

Crespo-García,

Cámara-Checa,

Dago

et al. 2022

Biochemical Pharmacology

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M3 Muscarinic Receptor Signaling Stabilizes a Novel Mutant Human Ether-a-Go-Go-Related Gene Channel Protein via Phosphorylation of Heat Shock Factor 1 in Transfected Cells

Cited by 6 publications

References 26 publications

Heat shock protein (Hsp) regulation by muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus

Heat shock protein (Hsp) regulation by muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus

Differential Regulation of Human Ether-à-Go-Go–Related Gene (hERG) Current and Expression by Activation of Protein Kinase C

Regulation of cardiac ion channels by transcription factors: Looking for new opportunities of druggable targets for the treatment of arrhythmias

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