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2022 ◽  
Author(s):  
Nick Platt ◽  
Dawn Shepherd ◽  
Yuzhe Weng ◽  
Grant Charles Churchill ◽  
Antony Galione ◽  
...  

The lysosome is a dynamic signaling organelle that is critical for cell functioning. It is a regulated calcium store that can contribute to Ca2+-regulated processes via both local calcium release and more globally by influencing ER Ca2+release. Here, we provide evidence from studies of an authentic mouse model of the lysosomal storage disease Niemann-Pick Type C (NPC) that has reduced lysosomal Ca2+ levels, and genetically modified mice in which the two-pore lysosomal Ca2+ release channel family are deleted that lysosomal Ca2+ signaling is required for normal pro-inflammatory responses. We demonstrate that production of the pro-inflammatory cytokine IL-1beta via the NLRP3 inflammasome is significantly reduced in murine Niemann-Pick Type C, the inhibition is selective because secretion of TNF alpha is not diminished, and it is a consequence of inefficient inflammasome priming. Synthesis of precursor ProIL-1 beta is significantly reduced in macrophages genetically deficient in the lysosomal protein Npc1, which is mutated in most clinical cases of NPC, and in wild type cells in which Npc1 activity is pharmacologically inhibited. Comparable reductions in ProIL-1 beta generation were measured in vitro and in vivo by macrophages genetically altered to lack expression of the two-pore lysosomal Ca2+ release channels Tpcn1 or Tpcn2. These data demonstrate a requirement for lysosome-dependent Ca2+ signaling in the generation of specific pro-inflammatory responses.


2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Qi Yuan ◽  
Haikel Dridi ◽  
Oliver B. Clarke ◽  
Steven Reiken ◽  
Zephan Melville ◽  
...  

AbstractThe type 1 ryanodine receptor (RyR1) is an intracellular calcium (Ca2+) release channel on the sarcoplasmic/endoplasmic reticulum that is required for skeletal muscle contraction. RyR1 channel activity is modulated by ligands, including the activators Ca2+ and ATP. Patients with inherited mutations in RyR1 may exhibit muscle weakness as part of a heterogeneous, complex disorder known as RYR1-related myopathy (RYR1-RM) or more recently termed RYR1-related disorders (RYR1-RD). Guided by high-resolution structures of skeletal muscle RyR1, obtained using cryogenic electron microscopy, we introduced mutations into putative Ca2+ and ATP binding sites and studied the function of the resulting mutant channels. These mutations confirmed the functional significance of the Ca2+ and ATP binding sites identified by structural studies based on the effects on channel regulation. Under normal conditions, Ca2+ activates RyR1 at low concentrations (µM) and inhibits it at high concentrations (mM). Mutations in the Ca2+-binding site impaired both activating and inhibitory regulation of the channel, suggesting a single site for both high and low affinity Ca2+-dependent regulation of RyR1 function. Mutation of residues that interact with the adenine ring of ATP abrogated ATP binding to the channel, whereas mutating residues that interact with the triphosphate tail only affected the degree of activation. In addition, patients with mutations at the Ca2+ or ATP binding sites suffer from muscle weakness, therefore impaired RyR1 channel regulation by either Ca2+ or ATP may contribute to the pathophysiology of RYR1-RM in some patients.


2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Matteo Serano ◽  
Laura Pietrangelo ◽  
Cecilia Paolini ◽  
Flavia A. Guarnier ◽  
Feliciano Protasi

Ryanodine receptor type-1 (RYR1) and Calsequestrin-1 (CASQ1) proteins, located in the sarcoplasmic reticulum (SR), are two of the main players in skeletal excitation–contraction (EC) coupling. Mutations in the human RYR1 gene (encoding for the SR Ca2+ release channel) and ablation in mice of CASQ1 (a SR Ca2+ binding protein) cause hypersensitivity to halogenated anesthetics (malignant hyperthermia [MH] susceptibility) and to heat (heat stroke; HS). As both MH and HS are characterized by excessive cytosolic Ca2+ levels and hypermetabolic responses, we studied the metabolism of 4-mo-old mice from two different lines that are MH/HS susceptible: knock-in mice carrying a human MH mutation (RYR1YS) and CASQ1-knockout (ko) mice. RYR1YS and, to a lesser degree, CASQ1-null mice show an increased volume of oxygen consumption (VO2) and a lower respiratory quotient (RQ) compared with WT mice (indicative of a metabolism that relies more on lipids). This finding is accompanied by a reduction in total body fat mass in both Y522S and CASQ1-null mice (again, compared with WT). In addition, we found that RYR1YS and CASQ1-null mice have an increased food consumption (+26.04% and +25.58% grams/day, respectively) and higher basal core temperature (+0.57°C and +0.54°C, respectively) compared with WT mice. Finally, Western blots and electron microscopy indicated that, in hyperthermic mice, (1) SERCA (used to remove myoplasmic Ca2+) and UCP3 (responsible for a thermogenic process that dissipates mitochondrial H+ gradient) are overexpressed, and (2) mitochondrial volume and percentage of damaged mitochondria are both increased. In conclusion, the MH/HS phenotype in RYR1YS and CASQ1-null mice is associated with an intrinsically increased basal metabolism.


2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Yvonne Sleiman ◽  
Alain Lacampagne ◽  
Albano C. Meli

AbstractThe regulation of intracellular calcium (Ca2+) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco/endoplasmic reticulum (SR/ER), plays a key role in the intracellular Ca2+ handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients’ cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient’s genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics.


2021 ◽  
Vol 22 (21) ◽  
pp. 11377
Author(s):  
Raquel Gómez-Oca ◽  
Belinda S. Cowling ◽  
Jocelyn Laporte

Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jean-Pierre Benitah ◽  
Romain Perrier ◽  
Jean-Jacques Mercadier ◽  
Laetitia Pereira ◽  
Ana M. Gómez

Heart Failure (HF) is defined as the inability of the heart to efficiently pump out enough blood to maintain the body's needs, first at exercise and then also at rest. Alterations in Ca2+ handling contributes to the diminished contraction and relaxation of the failing heart. While most Ca2+ handling protein expression and/or function has been shown to be altered in many models of experimental HF, in this review, we focus in the sarcoplasmic reticulum (SR) Ca2+ release channel, the type 2 ryanodine receptor (RyR2). Various modifications of this channel inducing alterations in its function have been reported. The first was the fact that RyR2 is less responsive to activation by Ca2+ entry through the L-Type calcium channel, which is the functional result of an ultrastructural remodeling of the ventricular cardiomyocyte, with fewer and disorganized transverse (T) tubules. HF is associated with an elevated sympathetic tone and in an oxidant environment. In this line, enhanced RyR2 phosphorylation and oxidation have been shown in human and experimental HF. After several controversies, it is now generally accepted that phosphorylation of RyR2 at the Calmodulin Kinase II site (S2814) is involved in both the depressed contractile function and the enhanced arrhythmic susceptibility of the failing heart. Diminished expression of the FK506 binding protein, FKBP12.6, may also contribute. While these alterations have been mostly studied in the left ventricle of HF with reduced ejection fraction, recent studies are looking at HF with preserved ejection fraction. Moreover, alterations in the RyR2 in HF may also contribute to supraventricular defects associated with HF such as sinus node dysfunction and atrial fibrillation.


2021 ◽  
Vol 22 (19) ◽  
pp. 10795
Author(s):  
Takuya Kobayashi ◽  
Nagomi Kurebayashi ◽  
Takashi Murayama

The ryanodine receptor (RyR) is a Ca2+ release channel in the sarcoplasmic reticulum of skeletal and cardiac muscles and plays a key role in excitation–contraction coupling. The activity of the RyR is regulated by the changes in the level of many intracellular factors, such as divalent cations (Ca2+ and Mg2+), nucleotides, associated proteins, and reactive oxygen species. Since these intracellular factors change depending on the condition of the muscle, e.g., exercise, fatigue, or disease states, the RyR channel activity will be altered accordingly. In this review, we describe how the RyR channel is regulated under various conditions and discuss the possibility that the RyR acts as a sensor for changes in the intracellular environments in muscles.


2021 ◽  
Vol 15 ◽  
Author(s):  
Ruyi Mei ◽  
Linyu Huang ◽  
Mengyuan Wu ◽  
Chunxia Jiang ◽  
Aifen Yang ◽  
...  

Myelination of neuronal axons in the central nervous system (CNS) by oligodendrocytes (OLs) enables rapid saltatory conductance and axonal integrity, which are crucial for normal brain functioning. Previous studies suggested that different subtypes of oligodendrocytes in the CNS form different types of myelin determined by the diameter of axons in the unit. However, the molecular mechanisms underlying the developmental association of different types of oligodendrocytes with different fiber sizes remain elusive. In the present study, we present the evidence that the intracellular Ca2+ release channel associated receptor (Itpr2) contributes to this developmental process. During early development, Itpr2 is selectively up-regulated in oligodendrocytes coinciding with the initiation of myelination. Functional analyses in both conventional and conditional Itpr2 mutant mice revealed that Itpr2 deficiency causes a developmental delay of OL differentiation, resulting in an increased percentage of CAII+ type I/II OLs which prefer to myelinate small-diameter axons in the CNS. The increased percentage of small caliber myelinated axons leads to an abnormal compound action potentials (CAP) in the optic nerves. Together, these findings revealed a previously unrecognized role for Itpr2-mediated calcium signaling in regulating the development of different types of oligodendrocytes.


2021 ◽  
Vol 15 ◽  
Author(s):  
Mark W. Sherwood ◽  
Misa Arizono ◽  
Aude Panatier ◽  
Katsuhiko Mikoshiba ◽  
Stéphane H. R. Oliet

Astrocytes are sensitive to ongoing neuronal/network activities and, accordingly, regulate neuronal functions (synaptic transmission, synaptic plasticity, behavior, etc.) by the context-dependent release of several gliotransmitters (e.g., glutamate, glycine, D-serine, ATP). To sense diverse input, astrocytes express a plethora of G-protein coupled receptors, which couple, via Gi/o and Gq, to the intracellular Ca2+ release channel IP3-receptor (IP3R). Indeed, manipulating astrocytic IP3R-Ca2+ signaling is highly consequential at the network and behavioral level: Depleting IP3R subtype 2 (IP3R2) results in reduced GPCR-Ca2+ signaling and impaired synaptic plasticity; enhancing IP3R-Ca2+ signaling affects cognitive functions such as learning and memory, sleep, and mood. However, as a result of discrepancies in the literature, the role of GPCR-IP3R-Ca2+ signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IP3R2 has been used to represent all astrocytic IP3Rs, including IP3R1 and IP3R3. Indeed, IP3R1 and IP3R3 are unique Ca2+ channels in their own right; they have unique biophysical properties, often display distinct distribution, and are differentially regulated. As a result, they mediate different physiological roles to IP3R2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca2+ dynamics and provide unique opportunities for integrating neuronal input and modulating astrocyte–neuron communication. The current review weighs evidence supporting the existence of multiple astrocytic-IP3R isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca2+ dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IP3R isoform.


2021 ◽  
Author(s):  
Bin Liu ◽  
Brian D. Tow ◽  
Ingrid M. Bonilla

The rhythmic contraction of the heart relies on tightly regulated calcium (Ca) release from the sarcoplasmic reticulum (SR) Ca release channel, Ryanodine receptor (RyR2). Genetic mutations in components of the calcium release unit such as RyR2, cardiac calsequestrin and other proteins have been shown to cause a genetic arrhythmic syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT). This book chapter will focus on the following: (1) to describing CPVT as a stress-induced cardiac arrhythmia syndrome and its genetic causes. (2) Discussing the regulation of SR Ca release, and how dysregulation of Ca release contributes to arrhythmogenesis. (3) Discussing molecular mechanisms of CPVT with a focus on impaired Ca signaling refractoriness as a unifying mechanism underlying different genetic forms of CPVT. (4) Discussing pharmacological approaches as CPVT treatments as well as other potential future therapies. Since dysregulated SR Ca release has been implicated in multiple cardiac disorders including heart failure and metabolic heart diseases, knowledge obtained from CPVT studies will also shed light on the development of therapeutic approaches for these devastating cardiac dysfunctions as a whole.


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