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Open AccessArticle

Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State

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Int. J. Mol. Sci. 2023, 24(16), 12547; https://doi.org/10.3390/ijms241612547 - 08 Aug 2023

Viewed by 374

Abstract

Ca²⁺ leak from cardiomyocyte sarcoplasmic reticulum (SR) via hyperactive resting cardiac ryanodine receptor channels (RyR2) is pro-arrhythmic. An exogenous peptide (DPc10) binding promotes leaky RyR2 in cardiomyocytes and reports on that endogenous state. Conversely, calmodulin (CaM) binding inhibits RyR2 leak and low [...] Read more.

Ca²⁺ leak from cardiomyocyte sarcoplasmic reticulum (SR) via hyperactive resting cardiac ryanodine receptor channels (RyR2) is pro-arrhythmic. An exogenous peptide (DPc10) binding promotes leaky RyR2 in cardiomyocytes and reports on that endogenous state. Conversely, calmodulin (CaM) binding inhibits RyR2 leak and low CaM affinity is diagnostic of leaky RyR2. These observations have led to designing a FRET biosensor for drug discovery targeting RyR2. We used FRET to clarify the molecular mechanism driving the DPc10-CaM interdependence when binding RyR2 in SR vesicles. We used donor-FKBP12.6 (D-FKBP) to resolve RyR2 binding of acceptor-CaM (A-CaM). In low nanomolar Ca²⁺, DPc10 decreased both FRET_max (under saturating [A-CaM]) and the CaM/RyR2 binding affinity. In micromolar Ca²⁺, DPc10 decreased FRET_max without affecting CaM/RyR2 binding affinity. This correlates with the analysis of fluorescence-lifetime-detected FRET, indicating that DPc10 lowers occupancy of the RyR2 CaM-binding sites in nanomolar (not micromolar) Ca²⁺ and lengthens D-FKBP/A-CaM distances independent of [Ca²⁺]. To observe DPc10/RyR2 binding, we used acceptor-DPc10 (A-DPc10). CaM weakens A-DPc10/RyR2 binding, with this effect being larger in micromolar versus nanomolar Ca²⁺. Moreover, A-DPc10/RyR2 binding is cooperative in a CaM- and FKBP-dependent manner, suggesting that both endogenous modulators promote concerted structural changes between RyR2 protomers for channel regulation. Aided by the analysis of cryo-EM structures, these insights inform further development of the DPc10-CaM paradigm for therapeutic discovery targeting RyR2. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessArticle

Inhibition of miR-25 Ameliorates Cardiac Dysfunction and Fibrosis by Restoring Krüppel-like Factor 4 Expression

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Cholong Lee

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Sunghye Cho

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Dongtak Jeong

Int. J. Mol. Sci. 2023, 24(15), 12434; https://doi.org/10.3390/ijms241512434 - 04 Aug 2023

Viewed by 536

Abstract

Cardiac hypertrophy is an adaptive response to various pathological insults, including hypertension. However, sustained hypertrophy can cause impaired calcium regulation, cardiac dysfunction, and remodeling, accompanied by cardiac fibrosis. Our previous study identified miR-25 as a regulator of SERCA2a, and found that the inhibition [...] Read more.

Cardiac hypertrophy is an adaptive response to various pathological insults, including hypertension. However, sustained hypertrophy can cause impaired calcium regulation, cardiac dysfunction, and remodeling, accompanied by cardiac fibrosis. Our previous study identified miR-25 as a regulator of SERCA2a, and found that the inhibition of miR-25 improved cardiac function and reduced fibrosis by restoring SERCA2a expression in a murine heart failure model. However, the precise mechanism underlying the reduction in fibrosis following miR-25 inhibition remains unclear. Therefore, we postulate that miR-25 may have additional targets that contribute to regulating cardiac fibrosis. Using in silico analysis, Krüppel-like factor 4 (KLF4) was identified as an additional target of miR-25. Further experiments confirmed that KLF4 was directly targeted by miR-25 and that its expression was reduced by long-term treatment with Angiotensin II, a major hypertrophic inducer. Subsequently, treatment with an miR-25 inhibitor alleviated the cardiac dysfunction, fibrosis, and inflammation induced by Angiotensin II (Ang II). These findings indicate that inhibiting miR-25 not only enhances calcium cycling and cardiac function via SERCA2a restoration but also reduces fibrosis by restoring KLF4 expression. Therefore, targeting miR-25 may be a promising therapeutic strategy for treating hypertensive heart diseases. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessArticle

Calcium Handling Remodeling Underlies Impaired Sympathetic Stress Response in Ventricular Myocardium from Cacna1c Haploinsufficient Rats

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Rainer K. W. Schwarting

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Int. J. Mol. Sci. 2023, 24(12), 9795; https://doi.org/10.3390/ijms24129795 - 06 Jun 2023

Viewed by 715

Abstract

CACNA1C encodes the pore-forming α1C subunit of the L-type Ca²⁺ channel, Cav1.2. Mutations and polymorphisms of the gene are associated with neuropsychiatric and cardiac disease. Haploinsufficient Cacna1c^+/− rats represent a recently developed model with a behavioral phenotype, but its cardiac phenotype [...] Read more.

CACNA1C encodes the pore-forming α1C subunit of the L-type Ca²⁺ channel, Cav1.2. Mutations and polymorphisms of the gene are associated with neuropsychiatric and cardiac disease. Haploinsufficient Cacna1c^+/− rats represent a recently developed model with a behavioral phenotype, but its cardiac phenotype is unknown. Here, we unraveled the cardiac phenotype of Cacna1c^+/− rats with a main focus on cellular Ca²⁺ handling mechanisms. Under basal conditions, isolated ventricular Cacna1c^+/− myocytes exhibited unaltered L-type Ca²⁺ current, Ca²⁺ transients (CaTs), sarcoplasmic reticulum (SR) Ca²⁺ load, fractional release, and sarcomere shortenings. However, immunoblotting of left ventricular (LV) tissue revealed reduced expression of Cav1.2, increased expression of SERCA2a and NCX, and augmented phosphorylation of RyR2 (at S2808) in Cacna1c^+/− rats. The β-adrenergic agonist isoprenaline increased amplitude and accelerated decay of CaTs and sarcomere shortenings in both Cacna1c^+/− and WT myocytes. However, the isoprenaline effect on CaT amplitude and fractional shortening (but not CaT decay) was impaired in Cacna1c^+/− myocytes exhibiting both reduced potency and efficacy. Moreover, sarcolemmal Ca²⁺ influx and fractional SR Ca²⁺ release after treatment with isoprenaline were smaller in Cacna1c^+/− than in WT myocytes. In Langendorff-perfused hearts, the isoprenaline-induced increase in RyR2 phosphorylation at S2808 and S2814 was attenuated in Cacna1c^+/− compared to WT hearts. Despite unaltered CaTs and sarcomere shortenings, Cacna1c^+/− myocytes display remodeling of Ca²⁺ handling proteins under basal conditions. Mimicking sympathetic stress with isoprenaline unmasks an impaired ability to stimulate Ca²⁺ influx, SR Ca²⁺ release, and CaTs caused, in part, by reduced phosphorylation reserve of RyR2 in Cacna1c^+/− cardiomyocytes. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessArticle

Calpain-3 Is Not a Sodium Dependent Protease and Simply Requires Calcium for Activation

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Stefan G. Wette

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Graham D. Lamb

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Robyn M. Murphy

Int. J. Mol. Sci. 2023, 24(11), 9405; https://doi.org/10.3390/ijms24119405 - 28 May 2023

Cited by 1 | Viewed by 796

Abstract

Calpain-3 (CAPN3) is a muscle-specific member of the calpain family of Ca²⁺-dependent proteases. It has been reported that CAPN3 can also be autolytically activated by Na⁺ ions in the absence of Ca²⁺, although this was only shown under [...] Read more.

Calpain-3 (CAPN3) is a muscle-specific member of the calpain family of Ca²⁺-dependent proteases. It has been reported that CAPN3 can also be autolytically activated by Na⁺ ions in the absence of Ca²⁺, although this was only shown under non-physiological ionic conditions. Here we confirm that CAPN3 does undergo autolysis in the presence of high [Na⁺], but this only occurred if all K⁺ normally present in a muscle cell was absent, and it did not occur even in 36 mM Na⁺, higher than what would ever be reached in exercising muscle if normal [K⁺] was present. CAPN3 in human muscle homogenates was autolytically activated by Ca²⁺, with ~50% CAPN3 autolysing in 60 min in the presence of 2 µM Ca²⁺. In comparison, autolytic activation of CAPN1 required about 5-fold higher [Ca²⁺] in the same conditions and tissue. After it was autolysed, CAPN3 unbound from its tight binding on titin and became diffusible, but only if the autolysis led to complete removal of the IS1 inhibitory peptide within CAPN3, reducing the C-terminal fragment to 55 kDa. Contrary to a previous report, activation of CAPN3, either by raised [Ca²⁺] or Na⁺ treatment, did not cause proteolysis of the skeletal muscle Ca²⁺ release channel-ryanodine receptor, RyR1, in physiological ionic conditions. Treatment of human muscle homogenates with high [Ca²⁺] caused autolytic activation of CAPN1, accompanied by proteolysis of some titin and complete proteolysis of junctophilin (JP1, full length ~95 kDa), generating an equimolar amount of a diffusible ~75 kDa N-terminal JP1 fragment, but without any proteolysis of RyR1. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessArticle

A Dominant-Negative Mutant of ANXA7 Impairs Calcium Signaling and Enhances the Proliferation of Prostate Cancer Cells by Downregulating the IP3 Receptor and the PI3K/mTOR Pathway

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Int. J. Mol. Sci. 2023, 24(10), 8818; https://doi.org/10.3390/ijms24108818 - 16 May 2023

Viewed by 681

Abstract

Annexin A7/ANXA7 is a calcium-dependent membrane fusion protein with tumor suppressor gene (TSG) properties, which is located on chromosome 10q21 and is thought to function in the regulation of calcium homeostasis and tumorigenesis. However, whether the molecular mechanisms for tumor suppression are also [...] Read more.

Annexin A7/ANXA7 is a calcium-dependent membrane fusion protein with tumor suppressor gene (TSG) properties, which is located on chromosome 10q21 and is thought to function in the regulation of calcium homeostasis and tumorigenesis. However, whether the molecular mechanisms for tumor suppression are also involved in the calcium- and phospholipid-binding properties of ANXA7 remain to be elucidated. We hypothesized that the 4 C-terminal endonexin-fold repeats in ANXA7 (GX(X)GT), which are contained within each of the 4 annexin repeats with 70 amino acids, are responsible for both calcium- and GTP-dependent membrane fusion and the tumor suppressor function. Here, we identified a dominant-negative triple mutant (DNTM/DN-ANXA7J) that dramatically suppressed the ability of ANXA7 to fuse with artificial membranes while also inhibiting tumor cell proliferation and sensitizing cells to cell death. We also found that the [DNTM]ANA7 mutation altered the membrane fusion rate and the ability to bind calcium and phospholipids. In addition, in prostate cancer cells, our data revealed that variations in phosphatidylserine exposure, membrane permeabilization, and cellular apoptosis were associated with differential IP3 receptor expression and PI3K/AKT/mTOR modulation. In conclusion, we discovered a triple mutant of ANXA7, associated with calcium and phospholipid binding, which leads to the loss of several essential functions of ANXA7 pertinent to tumor protection and highlights the importance of the calcium signaling and membrane fusion functions of ANXA7 for preventing tumorigenesis. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessArticle

Identification and Characterization of p300-Mediated Lysine Residues in Cardiac SERCA2a

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Int. J. Mol. Sci. 2023, 24(4), 3502; https://doi.org/10.3390/ijms24043502 - 09 Feb 2023

Cited by 1 | Viewed by 933

Abstract

Impaired calcium uptake resulting from reduced expression and activity of the cardiac sarco-endoplasmic reticulum Ca²⁺ ATPase (SERCA2a) is a hallmark of heart failure (HF). Recently, new mechanisms of SERCA2a regulation, including post-translational modifications (PTMs), have emerged. Our latest analysis of SERCA2a PTMs [...] Read more.

Impaired calcium uptake resulting from reduced expression and activity of the cardiac sarco-endoplasmic reticulum Ca²⁺ ATPase (SERCA2a) is a hallmark of heart failure (HF). Recently, new mechanisms of SERCA2a regulation, including post-translational modifications (PTMs), have emerged. Our latest analysis of SERCA2a PTMs has identified lysine acetylation as another PTM which might play a significant role in regulating SERCA2a activity. SERCA2a is acetylated, and that acetylation is more prominent in failing human hearts. In this study, we confirmed that p300 interacts with and acetylates SERCA2a in cardiac tissues. Several lysine residues in SERCA2a modulated by p300 were identified using in vitro acetylation assay. Analysis of in vitro acetylated SERCA2a revealed several lysine residues in SERCA2a susceptible to acetylation by p300. Among them, SERCA2a Lys514 (K514) was confirmed to be essential for SERCA2a activity and stability using an acetylated mimicking mutant. Finally, the reintroduction of an acetyl-mimicking mutant of SERCA2a (K514Q) into SERCA2 knockout cardiomyocytes resulted in deteriorated cardiomyocyte function. Taken together, our data demonstrated that p300-mediated acetylation of SERCA2a is a critical PTM that decreases the pump’s function and contributes to cardiac impairment in HF. SERCA2a acetylation can be targeted for therapeutic aims for the treatment of HF. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessArticle

Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic Circulation

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Int. J. Mol. Sci. 2022, 23(23), 14941; https://doi.org/10.3390/ijms232314941 - 29 Nov 2022

Cited by 3 | Viewed by 1437

Abstract

Calciprotein particles (CPPs) represent an inherent mineral buffering system responsible for the scavenging of excessive Ca²⁺ and PO₄³⁻ ions in order to prevent extraskeletal calcification, although contributing to the development of endothelial dysfunction during the circulation in the bloodstream. Here, [...] Read more.

Calciprotein particles (CPPs) represent an inherent mineral buffering system responsible for the scavenging of excessive Ca²⁺ and PO₄³⁻ ions in order to prevent extraskeletal calcification, although contributing to the development of endothelial dysfunction during the circulation in the bloodstream. Here, we performed label-free proteomic profiling to identify the functional consequences of CPP internalisation by endothelial cells (ECs) and found molecular signatures of significant disturbances in mitochondrial and lysosomal physiology, including oxidative stress, vacuolar acidification, accelerated proteolysis, Ca²⁺ cytosolic elevation, and mitochondrial outer membrane permeabilisation. Incubation of intact ECs with conditioned medium from CPP-treated ECs caused their pro-inflammatory activation manifested by vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) upregulation and elevated release of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1/ C-C motif ligand 2 (MCP-1/CCL2). Among the blood cells, monocytes were exclusively responsible for CPP internalisation. As compared to the co-incubation of donor blood with CPPs in the flow culture system, intravenous administration of CPPs to Wistar rats caused a considerably higher production of chemokines, indicating the major role of monocytes in CPP-triggered inflammation. Upregulation of sICAM-1 and IL-8 also suggested a notable contribution of endothelial dysfunction to systemic inflammatory response after CPP injections. Collectively, our results demonstrate the pathophysiological significance of CPPs and highlight the need for the development of anti-CPP therapies. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Review

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Open AccessReview

Calpain Regulation and Dysregulation—Its Effects on the Intercalated Disk

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Micah W. Yoder

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Nathan T. Wright

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Maegen A. Borzok

Int. J. Mol. Sci. 2023, 24(14), 11726; https://doi.org/10.3390/ijms241411726 - 21 Jul 2023

Viewed by 500

Abstract

The intercalated disk is a cardiac specific structure composed of three main protein complexes—adherens junctions, desmosomes, and gap junctions—that work in concert to provide mechanical stability and electrical synchronization to the heart. Each substructure is regulated through a variety of mechanisms including proteolysis. [...] Read more.

The intercalated disk is a cardiac specific structure composed of three main protein complexes—adherens junctions, desmosomes, and gap junctions—that work in concert to provide mechanical stability and electrical synchronization to the heart. Each substructure is regulated through a variety of mechanisms including proteolysis. Calpain proteases, a class of cysteine proteases dependent on calcium for activation, have recently emerged as important regulators of individual intercalated disk components. In this review, we will examine how calcium homeostasis regulates normal calpain function. We will also explore how calpains modulate gap junctions, desmosomes, and adherens junctions activity by targeting specific proteins, and describe the molecular mechanisms of how calpain dysregulation leads to structural and signaling defects within the heart. We will then examine how changes in calpain activity affects cardiomyocytes, and how such changes underlie various heart diseases. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessReview

Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle

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Bianca S. Romero-Martínez

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Bettina Sommer

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Héctor Solís-Chagoyán

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Eduardo Calixto

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Arnoldo Aquino-Gálvez

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Ruth Jaimez

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Juan C. Gomez-Verjan

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Georgina González-Avila

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Edgar Flores-Soto

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Luis M. Montaño

Int. J. Mol. Sci. 2023, 24(9), 7879; https://doi.org/10.3390/ijms24097879 - 26 Apr 2023

Viewed by 1318

Abstract

To preserve ionic homeostasis (primarily Ca²⁺, K⁺, Na⁺, and Cl⁻), in the airway smooth muscle (ASM) numerous transporters (channels, exchangers, and pumps) regulate the influx and efflux of these ions. Many of intracellular processes depend [...] Read more.

To preserve ionic homeostasis (primarily Ca²⁺, K⁺, Na⁺, and Cl⁻), in the airway smooth muscle (ASM) numerous transporters (channels, exchangers, and pumps) regulate the influx and efflux of these ions. Many of intracellular processes depend on continuous ionic permeation, including exocytosis, contraction, metabolism, transcription, fecundation, proliferation, and apoptosis. These mechanisms are precisely regulated, for instance, through hormonal activity. The lipophilic nature of steroidal hormones allows their free transit into the cell where, in most cases, they occupy their cognate receptor to generate genomic actions. In the sense, estrogens can stimulate development, proliferation, migration, and survival of target cells, including in lung physiology. Non-genomic actions on the other hand do not imply estrogen’s intracellular receptor occupation, nor do they initiate transcription and are mostly immediate to the stimulus. Among estrogen’s non genomic responses regulation of calcium homeostasis and contraction and relaxation processes play paramount roles in ASM. On the other hand, disruption of calcium homeostasis has been closely associated with some ASM pathological mechanism. Thus, this paper intends to summarize the effects of estrogen on ionic handling proteins in ASM. The considerable diversity, range and power of estrogens regulates ionic homeostasis through genomic and non-genomic mechanisms. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessReview

The Role of the Piezo1 Mechanosensitive Channel in the Musculoskeletal System

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Int. J. Mol. Sci. 2023, 24(7), 6513; https://doi.org/10.3390/ijms24076513 - 30 Mar 2023

Cited by 1 | Viewed by 1364

Abstract

Since the recent discovery of the mechanosensitive Piezo1 channels, many studies have addressed the role of the channel in various physiological or even pathological processes of different organs. Although the number of studies on their effects on the musculoskeletal system is constantly increasing, [...] Read more.

Since the recent discovery of the mechanosensitive Piezo1 channels, many studies have addressed the role of the channel in various physiological or even pathological processes of different organs. Although the number of studies on their effects on the musculoskeletal system is constantly increasing, we are still far from a precise understanding. In this review, the knowledge available so far regarding the musculoskeletal system is summarized, reviewing the results achieved in the field of skeletal muscles, bones, joints and cartilage, tendons and ligaments, as well as intervertebral discs. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessReview

Molecular Mechanisms and Pathophysiological Significance of Eryptosis

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Sumiah A. Alghareeb

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Mohammad A. Alfhili

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Sabiha Fatima

Int. J. Mol. Sci. 2023, 24(6), 5079; https://doi.org/10.3390/ijms24065079 - 07 Mar 2023

Cited by 4 | Viewed by 1758

Abstract

Despite lacking the central apoptotic machinery, senescent or damaged RBCs can undergo an unusual apoptosis-like cell death, termed eryptosis. This premature death can be caused by, or a symptom of, a wide range of diseases. However, various adverse conditions, xenobiotics, and endogenous mediators [...] Read more.

Despite lacking the central apoptotic machinery, senescent or damaged RBCs can undergo an unusual apoptosis-like cell death, termed eryptosis. This premature death can be caused by, or a symptom of, a wide range of diseases. However, various adverse conditions, xenobiotics, and endogenous mediators have also been recognized as triggers and inhibitors of eryptosis. Eukaryotic RBCs are unique among their cell membrane distribution of phospholipids. The change in the RBC membrane composition of the outer leaflet occurs in a variety of diseases, including sickle cell disease, renal diseases, leukemia, Parkinson’s disease, and diabetes. Eryptotic erythrocytes exhibit various morphological alterations such as shrinkage, swelling, and increased granulation. Biochemical changes include cytosolic Ca²⁺ increase, oxidative stress, stimulation of caspases, metabolic exhaustion, and ceramide accumulation. Eryptosis is an effective mechanism for the elimination of dysfunctional erythrocytes due to senescence, infection, or injury to prevent hemolysis. Nevertheless, excessive eryptosis is associated with multiple pathologies, most notably anemia, abnormal microcirculation, and prothrombotic risk; all of which contribute to the pathogenesis of several diseases. In this review, we provide an overview of the molecular mechanisms, physiological and pathophysiological relevance of eryptosis, as well as the potential role of natural and synthetic compounds in modulating RBC survival and death. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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Open AccessPerspective

Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms

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Jana Gaburjakova

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Marta Gaburjakova

Int. J. Mol. Sci. 2023, 24(6), 5409; https://doi.org/10.3390/ijms24065409 - 12 Mar 2023

Cited by 1 | Viewed by 965

Abstract

Dantrolene is an intra-cellularly acting skeletal muscle relaxant used for the treatment of the rare genetic disorder, malignant hyperthermia (MH). In most cases, MH susceptibility is caused by dysfunction of the skeletal ryanodine receptor (RyR1) harboring one of nearly 230 single-point MH mutations. [...] Read more.

Dantrolene is an intra-cellularly acting skeletal muscle relaxant used for the treatment of the rare genetic disorder, malignant hyperthermia (MH). In most cases, MH susceptibility is caused by dysfunction of the skeletal ryanodine receptor (RyR1) harboring one of nearly 230 single-point MH mutations. The therapeutic effect of dantrolene is the result of a direct inhibitory action on the RyR1 channel, thus suppressing aberrant Ca²⁺ release from the sarcoplasmic reticulum. Despite the almost identical dantrolene-binding sequence exits in all three mammalian RyR isoforms, dantrolene appears to be an isoform-selective inhibitor. Whereas RyR1 and RyR3 channels are competent to bind dantrolene, the RyR2 channel, predominantly expressed in the heart, is unresponsive. However, a large body of evidence suggests that the RyR2 channel becomes sensitive to dantrolene-mediated inhibition under certain pathological conditions. Although a consistent picture of the dantrolene effect emerges from in vivo studies, in vitro results are often contradictory. Hence, our goal in this perspective is to provide the best possible clues to the molecular mechanism of dantrolene’s action on RyR isoforms by identifying and discussing potential sources of conflicting results, mainly coming from cell-free experiments. Moreover, we propose that, specifically in the case of the RyR2 channel, its phosphorylation could be implicated in acquiring the channel responsiveness to dantrolene inhibition, interpreting functional findings in the structural context. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)

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