Store-operated calcium entry: From physiology to tubular aggregate myopathy

Protasi, Feliciano; Girolami, Barbara; Roccabianca, Sara; Rossi, Daniela

doi:10.1016/j.coph.2022.102347

Cited by 10 publications

(8 citation statements)

References 180 publications

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“…The Stormorken syndrome clinically overlaps with TAM, a progressive muscle disorder associated with weakness, cramps, myalgia, increased creatine kinase levels, and accumulation of packed membrane tubules containing sarcoplasmic reticulum proteins. These tubules are observed by electron microscopy as straight, single- or double-walled tubules that are highly ordered and aligned in parallel in a longitudinal muscle section [ 56 , 57 ]. Furthermore, TAM is characterized by large variations in fiber size, increased number of fibers with internalized nuclei, as well as type 1 fiber predominance [ 58 ].…”

Section: Disorders Associated With Gain-of-function Stim1 Mutationsmentioning

confidence: 99%

The Ca2+ Sensor STIM in Human Diseases

Berna-Erro,

Sanchez-Collado,

Nieto-Felipe

et al. 2023

Biomolecules

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The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca2+ entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca2+ sensors in the endoplasmic reticulum (ER) and, upon Ca2+ store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca2+ signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca2+ signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects.

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Section: Disorders Associated With Gain-of-function Stim1 Mutationsmentioning

confidence: 99%

The Ca2+ Sensor STIM in Human Diseases

Berna-Erro,

Sanchez-Collado,

Nieto-Felipe

et al. 2023

Biomolecules

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“…SOCE is either down-regulated or up-regulated in a growing number of disorders, including severe combined immunodeficiency [ 119 ], neurodegenerative diseases [ 120 ], genetic myopathies [ 121 ], pulmonary arterial hypertension [ 122 ], and cancer [ 123 ]. Preliminary evidence indicated that, even though Orai1 is weakly expressed in adult ventricular cardiomyocytes from humans and mice, its expression increases and leads to SOCE up-regulation in cardiac hypertrophy and heart failure [ 124 ].…”

Section: Flecainide Inhibits Soce and Prevents Ca 2+ ...mentioning

confidence: 99%

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy

Moccia

Brunetti

Soda

et al. 2023

JCM

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Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder that may lead patients to sudden cell death through the occurrence of ventricular arrhythmias. ACM is characterised by the progressive substitution of cardiomyocytes with fibrofatty scar tissue that predisposes the heart to life-threatening arrhythmic events. Cardiac mesenchymal stromal cells (C-MSCs) contribute to the ACM by differentiating into fibroblasts and adipocytes, thereby supporting aberrant remodelling of the cardiac structure. Flecainide is an Ic antiarrhythmic drug that can be administered in combination with β-adrenergic blockers to treat ACM due to its ability to target both Nav1.5 and type 2 ryanodine receptors (RyR2). However, a recent study showed that flecainide may also prevent fibro-adipogenic differentiation by inhibiting store-operated Ca2+ entry (SOCE) and thereby suppressing spontaneous Ca2+ oscillations in C-MSCs isolated from human ACM patients (ACM C-hMSCs). Herein, we briefly survey ACM pathogenesis and therapies and then recapitulate the main molecular mechanisms targeted by flecainide to mitigate arrhythmic events, including Nav1.5 and RyR2. Subsequently, we describe the role of spontaneous Ca2+ oscillations in determining MSC fate. Next, we discuss recent work showing that spontaneous Ca2+ oscillations in ACM C-hMSCs are accelerated to stimulate their fibro-adipogenic differentiation. Finally, we describe the evidence that flecainide suppresses spontaneous Ca2+ oscillations and fibro-adipogenic differentiation in ACM C-hMSCs by inhibiting constitutive SOCE.

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“…This induces cellular entry of Ca 2+ , which is then transported back to the ER by sarcoendoplasmic reticulum calcium ATPase (SERCA) pumps 19 . The importance of SOCE in muscle is evident as mutations in STIM1 or ORAI1 cause muscle diseases [20][21][22] . However, the physiological importance of this relatively small Ca 2+ influx as compared to the large intracellular Ca 2+ stores remains highly debated [23][24][25][26][27][28][29] .…”

Section: Introductionmentioning

confidence: 99%

mTORC1-dependent SOCE activity regulates synaptic gene expression and muscle response to denervation

Prola,

Dupont,

Rajendran

et al. 2024

Preprint

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Neuromuscular junction (NMJ) instability is central in muscle dysfunction occurring in neuromuscular disorders and aging. NMJ maintenance requires regionalized regulation of synaptic genes, previously associated with Ca2+-dependent pathways. However, what sustains Ca2+micro-domains in myofibers and allows a rapid response to denervation is not known. Here, we identify that Store-Operated Calcium Entry (SOCE) plays a critical role in synaptic gene regulation. SOCE components show differential enrichment in sub- and non-synaptic muscle regions. Especially, STIM1 accumulation at rough endoplasmic reticulum associates with functional SOCE at the endplate. Denervation increases SOCE in non- and sub- synaptic regions, together with reticulum remodeling.Stim1knockdown hampers denervation-induced synaptic gene up-regulation, while STIM1 overexpression increases synaptic gene expression in innervated muscle. Finally, mTORC1 activation mimics the effect of denervation on SOCE capacity, STIM1 localization and reticulum remodeling. Together, our results reveal a decisive role of SOCE in sensing innervation and regulating muscle response to denervation. They further suggest that SOCE perturbation may contribute to neuromuscular integrity loss in pathological conditions associated with mTORC1 dysregulation.

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Store-operated calcium entry: From physiology to tubular aggregate myopathy

Cited by 10 publications

References 180 publications

The Ca2+ Sensor STIM in Human Diseases

The Ca2+ Sensor STIM in Human Diseases

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy

mTORC1-dependent SOCE activity regulates synaptic gene expression and muscle response to denervation

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