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Medecine Sciences : M/S May 2024
Topics: Heart Failure; Humans; Ryanodine Receptor Calcium Release Channel; Animals
PubMed: 38819276
DOI: 10.1051/medsci/2024056 -
Human Molecular Genetics May 2024
PubMed: 38815237
DOI: 10.1093/hmg/ddae091 -
Frontiers in Cellular Neuroscience 2024Intracellular Ca-signaling in astrocytes is instrumental for their brain "housekeeping" role and astroglial control of synaptic plasticity. An important source for...
Intracellular Ca-signaling in astrocytes is instrumental for their brain "housekeeping" role and astroglial control of synaptic plasticity. An important source for elevating the cytosolic Ca level in astrocytes is a release from endoplasmic reticulum which can be triggered via two fundamental pathways: IP3 receptors and calcium-induced calcium release (CICR) mediated by Ca-sensitive ryanodine receptors (RyRs). While the physiological role for glial IP3 became a focus of intensive research and debate, ryanodine receptors received much less attention. We explored the role for ryanodine receptors in the modulation of cytosolic Ca-signaling in the cortical and hippocampal astrocytes, astrocyte-neuron communication and astroglia modulation of synaptic plasticity. Our data show that RyR-mediated Ca-induced Ca-release from ER brings substantial contribution into signaling in the functional microdomains hippocampal and neocortical astrocytes. Furthermore, RyR-mediated CICR activated the release of ATP and glutamate from hippocampal and neocortical astrocytes which, in turn, elicited transient purinergic and tonic glutamatergic currents in the neighboring pyramidal neurons. The CICR-facilitated release of ATP and glutamate was inhibited after intracellular perfusion of astrocytes with ryanodine and BAPTA and in the transgenic dnSNARE mice with impaired astroglial exocytosis. We also found out that RyR-mediated amplification of astrocytic Ca-signaling enhanced the long-term synaptic potentiation in the hippocampus and neocortex of aged mice. Combined, our data demonstrate that ryanodine receptors are essential for astrocytic Ca-signaling and efficient astrocyte-neuron communications. The RyR-mediated CICR contributes to astrocytic control of synaptic plasticity and can underlie, at least partially, neuroprotective and cognitive effects of caffein.
PubMed: 38812795
DOI: 10.3389/fncel.2024.1382010 -
Comparative Biochemistry and... Sep 2024Regional endothermy is the ability of an animal to elevate the temperature of specific regions of the body above that of the surrounding environment and has evolved...
Relative sarcolipin (SLN) and sarcoplasmic reticulum Ca ATPase (SERCA1) transcripts levels in closely related endothermic and ectothermic scombrid fishes: Implications for molecular basis of futile calcium cycle non-shivering thermogenesis (NST).
Regional endothermy is the ability of an animal to elevate the temperature of specific regions of the body above that of the surrounding environment and has evolved independently among several fish lineages. Sarcolipin (SLN) is a small transmembrane protein that uncouples the sarcoplasmic reticulum calcium ATPase pump (SERCA1b) resulting in futile Ca cycling and is thought to play a role in non-shivering thermogenesis (NST) in cold-challenged mammals and possibly some fishes. This study investigated the relative expression of sln and serca1 transcripts in three regionally-endothermic fishes (the skipjack, Katsuwonus pelamis, and yellowfin tuna, Thunnus albacares, both of which elevate the temperatures of their slow-twitch red skeletal muscle (RM) and extraocular muscles (EM), as well as the cranial endothermic swordfish, Xiphias gladius), and closely related ectothermic scombrids (the Eastern Pacific bonito, Sarda chiliensis, and Pacific chub mackerel, Scomber japonicus). Using Reverse Transcription quantitative PCR (RT-qPCR) and species-specific primers, relative sln expression trended higher in both the RM and EM for all four scombrid species compared to white muscle. In addition, relative serca1 expression was found to be higher in RM of skipjack and yellowfin tuna in comparison to white muscle. However, neither sln nor serca1 transcripts were higher in swordfish RM, EM or cranial heater tissue in comparison to white muscle. A key phosphorylation site in sarcolipin, threonine 5, is conserved in the swordfish, but is mutated to alanine or valine in tunas and the endothermic smalleye Pacific opah, Lampris incognitus, which should result in increased uncoupling of the SERCA pump. Our results support the role of potential SLN-NST in endothermic tunas and the lack thereof for swordfish.
Topics: Animals; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Proteolipids; Muscle Proteins; Thermogenesis; Calcium; Fish Proteins; Muscle, Skeletal; RNA, Messenger; Perciformes; Tuna
PubMed: 38782254
DOI: 10.1016/j.cbpa.2024.111667 -
Cardiovascular Research May 2024Gene therapy with cardiac phosphodiesterases (PDEs) such as PDE4B has recently been described to effectively prevent heart failure in mice. However, exact molecular...
AIMS
Gene therapy with cardiac phosphodiesterases (PDEs) such as PDE4B has recently been described to effectively prevent heart failure in mice. However, exact molecular mechanisms of its beneficial effects, apart from general lowering of cardiomyocyte cyclic adenosine monophosphate (cAMP) levels, have not been elucidated. Here we studied whether gene therapy with two types of PDEs, namely PDE2A and PDE4B, can prevent pressure-overload induced heart failure in mice by acting on and restoring altered cAMP compartmentalization in distinct subcellular microdomains.
METHODS AND RESULTS
Heart failure was induced by transverse aortic constriction followed by tail-vein injection of adeno-associated-virus type 9 vectors to overexpress PDE2A3, PDE4B3 or luciferase for 8 weeks. Heart morphology and function was assessed by echocardiography and histology which showed that PDE2A and especially PDE4B gene therapy could attenuate cardiac hypertrophy, fibrosis and decline of contractile function. Live cell imaging using targeted cAMP biosensors showed that PDE overexpression restored altered cAMP compartmentalization in microdomains associated with ryanodine receptor type 2 (RyR2) and caveolin-rich plasma membrane. This was accompanied by ameliorated caveolin-3 decline after PDE2A3 overexpression, reduced RyR2 phosphorylation in PDE4B3 overexpressing hearts and antiarrhythmic effects of both PDEs measured under isoproterenol stimulation in single cells. Strong association of overexpressed PDE4B but not PDE2A with RyR2 microdomain could prevent calcium leak and arrhythmias in human induced pluripotent stem derived cardiomyocytes with the A2254 V mutation in RyR2 causing catecholaminergic polymorphic ventricular tachycardia.
CONCLUSIONS
Our data indicate that gene therapy with phosphodiesterases can prevent heart failure including associated cardiac remodeling and arrhythmias by restoring altered cAMP compartmentalization in functionally relevant subcellular microdomains.
PubMed: 38776406
DOI: 10.1093/cvr/cvae094 -
British Journal of Pharmacology May 2024The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca homeostasis in cells in these organs....
BACKGROUND AND PURPOSE
The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.
EXPERIMENTAL APPROACH
Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca leak via RyR2 and intracellular Ca concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.
KEY RESULTS
In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.
CONCLUSIONS AND IMPLICATIONS
The novel drug M201-A inhibited diastolic Ca leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.
PubMed: 38773354
DOI: 10.1111/bph.16379 -
Journal of Neurochemistry May 2024Huntington's disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons in the striatum and cortex degenerate, leading to motor,...
Huntington's disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons in the striatum and cortex degenerate, leading to motor, psychiatric and cognitive disorders. Dysregulated synaptic function and calcium handling are common in many neurodegenerative diseases, including HD. N-methyl-D-aspartate (NMDA) receptor function is enhanced in HD at extrasynaptic sites, altering the balance of calcium-dependent neuronal survival versus death signalling pathways. Endoplasmic reticulum (ER) calcium handling is also abnormal in HD. The ER, which is continuous with the nuclear envelope, is purportedly involved in nuclear calcium signalling; based on this, we hypothesised that nuclear calcium signalling is altered in HD. We explored this hypothesis with calcium imaging techniques, including simultaneous epifluorescent imaging of cytosolic and nuclear calcium using jRCaMP1b and GCaMP3 sensors, respectively, in striatal spiny projection neurons in cortical-striatal co-cultures from the YAC128 mouse model of HD. Our data show contributions from a variety of calcium channels to nuclear calcium signalling. NMDA receptors (NMDARs) play an essential role in initiating action potential-dependent calcium signalling to the nucleus, and ryanodine receptors (RyR) contribute to both cytosolic and nuclear calcium signals. Unlike previous reports in glutamatergic hippocampal and cortical neurons, we found that in GABAergic striatal neurons, L-type voltage-gated calcium channels (CaV) contribute to cytosolic, but not nuclear calcium signalling. Calcium imaging also suggests impairments in nuclear calcium signalling in HD striatal neurons, where spontaneous action potential-dependent calcium transients in the nucleus were smaller in YAC128 striatal neurons compared to those of wild-type (WT). Our results elucidate mechanisms involved in action potential-dependent nuclear calcium signalling in GABAergic striatal neurons, and have revealed a clear deficit in this signalling in HD.
PubMed: 38770573
DOI: 10.1111/jnc.16132 -
Communications Biology May 2024Glycerophosphocholine (GPC) is an important precursor for intracellular choline supply in phosphatidylcholine (PC) metabolism. GDE5/Gpcpd1 hydrolyzes GPC into choline...
Glycerophosphocholine (GPC) is an important precursor for intracellular choline supply in phosphatidylcholine (PC) metabolism. GDE5/Gpcpd1 hydrolyzes GPC into choline and glycerol 3-phosphate; this study aimed to elucidate its physiological function in vivo. Heterozygous whole-body GDE5-deficient mice reveal a significant GPC accumulation across tissues, while homozygous whole-body knockout results in embryonic lethality. Skeletal muscle-specific GDE5 deletion (Gde5 skKO) exhibits reduced passive force and improved fatigue resistance in electrically stimulated gastrocnemius muscles in vivo. GDE5 deficiency also results in higher glycolytic metabolites and glycogen levels, and glycerophospholipids alteration, including reduced levels of phospholipids that bind polyunsaturated fatty acids (PUFAs), such as DHA. Interestingly, this PC fatty acid compositional change is similar to that observed in skeletal muscles of denervated and Duchenne muscular dystrophy mouse models. These are accompanied by decrease of GDE5 expression, suggesting a regulatory role of GDE5 activity for glycerophospholipid profiles. Furthermore, a DHA-rich diet enhances contractile force and lowers fatigue resistance, suggesting a functional relationship between PC fatty acid composition and muscle function. Finally, skinned fiber experiments show that GDE5 loss increases the probability of the ryanodine receptor opening and lowers the maximum Ca-activated force. Collectively, GDE5 activity plays roles in PC and glucose/glycogen metabolism in skeletal muscle.
Topics: Animals; Muscle, Skeletal; Mice; Phosphatidylcholines; Mice, Knockout; Muscle Contraction; Male; Mice, Inbred C57BL; Phosphoric Diester Hydrolases
PubMed: 38769369
DOI: 10.1038/s42003-024-06298-z -
Biochemical and Biophysical Research... Aug 2024Dexmedetomidine (DEX), a highly selective α2-adrenoceptor agonist, can decrease the incidence of arrhythmias, such as catecholaminergic polymorphic ventricular...
BACKGROUND
Dexmedetomidine (DEX), a highly selective α2-adrenoceptor agonist, can decrease the incidence of arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the underlying mechanisms by which DEX affects cardiac electrophysiological function remain unclear.
METHODS
Ryanodine receptor (RyR2) heterozygous R2474S mice were used as a model for CPVT. WT and RyR2 mice were treated with isoproterenol (ISO) and DEX, and electrocardiograms were continuously monitored during both in vivo and ex vivo experiments. Dual-dye optical mapping was used to explore the anti-arrhythmic mechanism of DEX.
RESULTS
DEX significantly reduced the occurrence and duration of ISO-induced of VT/VF in RyR2 mice in vivo and ex vivo. DEX remarkably prolonged action potential duration (APD) and calcium transient duration (CaTD) in both RyR2 and WT hearts, whereas it reduced APD heterogeneity and CaT alternans in RyR2 hearts. DEX inhibited ectopy and reentry formation, and stabilized voltage-calcium latency.
CONCLUSION
DEX exhibited an antiarrhythmic effect through stabilizing membrane voltage and intracellular Ca. DEX can be used as a beneficial perioperative anesthetic for patients with CPVT or other tachy-arrhythmias.
Topics: Animals; Dexmedetomidine; Ryanodine Receptor Calcium Release Channel; Calcium; Mice; Arrhythmias, Cardiac; Membrane Potentials; Isoproterenol; Tachycardia, Ventricular; Anti-Arrhythmia Agents; Male; Action Potentials; Mice, Inbred C57BL
PubMed: 38754163
DOI: 10.1016/j.bbrc.2024.150105 -
Nature Communications May 2024RyR1 is an intracellular Ca channel important in excitable cells such as neurons and muscle fibers. Ca activates it at low concentrations and inhibits it at high...
RyR1 is an intracellular Ca channel important in excitable cells such as neurons and muscle fibers. Ca activates it at low concentrations and inhibits it at high concentrations. Mg is the main physiological RyR1 inhibitor, an effect that is overridden upon activation. Despite the significance of Mg-mediated inhibition, the molecular-level mechanisms remain unclear. In this work we determined two cryo-EM structures of RyR1 with Mg up to 2.8 Å resolution, identifying multiple Mg binding sites. Mg inhibits at the known Ca activating site and we propose that the EF hand domain is an inhibitory divalent cation sensor. Both divalent cations bind to ATP within a crevice, contributing to the precise transmission of allosteric changes within the enormous channel protein. Notably, Mg inhibits RyR1 by interacting with the gating helices as validated by molecular dynamics. This structural insight enhances our understanding of how Mg inhibition is overcome during excitation.
Topics: Ryanodine Receptor Calcium Release Channel; Magnesium; Calcium; Cryoelectron Microscopy; Binding Sites; Animals; Molecular Dynamics Simulation; Adenosine Triphosphate; Humans; Rabbits
PubMed: 38750013
DOI: 10.1038/s41467-024-48292-3