scholarly journals David Herman Maclennan. 3 July 1937—24 June 2020

2021 ◽  
Author(s):  
Reinhart Reithmeier
Keyword(s):  
Muscle Contraction ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
New Technologies ◽  
Muscle Disease ◽  
Mitochondrial Atpase ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Isolation And Characterization ◽  
The University

David Herman MacLennan, one of Canada's foremost biomedical scientists, was known internationally for his research on the molecular mechanism of muscle contraction in human health and disease. David was born on 3 July 1937 in Swan River, Manitoba, and grew up in farm country. After obtaining a BS (Agriculture) in plant science from the University of Manitoba in 1959, David completed his MSc (1961) and PhD (1963) in biology at Purdue. A post-doctoral fellowship at the Enzyme Institute at the University of Wisconsin followed, where he was appointed as an assistant professor (1964–1968). At Wisconsin David published a series of elegant papers on the isolation and characterization of the mitochondrial ATPase and protein components of the electron transfer system. In 1969 he was recruited back to Canada as an associate professor in the Banting and Best Department of Medical Research at the University of Toronto, where he spent the rest of his illustrious career. Here, David shifted his focus to determine how calcium regulates muscle contraction, with a focus on the role of the sarcoplasmic reticulum (SR). David was a scientist who knew where a field was going and he often got there first, incorporating new technologies along the way. His early discovery of the Ca 2+ ATPase pump that controls calcium uptake into the SR was the key to muscle relaxation. His lab systematically characterized the components of the SR, including the ryanodine receptor which acts as a calcium release channel to allow muscle contraction. David's discoveries of these molecular mechanisms and their application to debilitating muscle disease are an inspiring scientific legacy. Although David published hundreds of papers, many cited hundreds of times, gave hundreds of invited seminars and won many prestigious awards, including Fellow of the Royal Society of London in 1994, his greatest legacy is the people he trained, many of whom went on to leadership positions in research and at universities around the world.

scholarly journals Phosphorylation-Dependent Interactome of Ryanodine Receptor Type 2 in the Heart

Proteomes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 27
Author(s):  
David Y. Chiang ◽  
Satadru Lahiri ◽  
Guoliang Wang ◽  
Jason Karch ◽  
Meng C. Wang ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Affinity Purification ◽  
Receptor Type ◽  
Mouse Heart ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Western Blots

Hyperphosphorylation of the calcium release channel/ryanodine receptor type 2 (RyR2) at serine 2814 (S2814) is associated with multiple cardiac diseases including atrial fibrillation and heart failure. Despite recent advances, the molecular mechanisms driving pathological changes associated with RyR2 S2814 phosphorylation are still not well understood. Methods: Using affinity-purification coupled to mass spectrometry (AP-MS), we investigated the RyR2 interactome in ventricles from wild-type (WT) mice and two S2814 knock-in mutants: the unphosphorylated alanine mutant (S2814A) and hyperphosphorylated mimic aspartic acid mutant (S2814D). Western blots were used for validation. Results: In WT mouse ventricular lysates, we identified 22 proteins which were enriched with RyR2 pull-down relative to both IgG control and no antibody (beads-only) pull-downs. Parallel AP-MS using WT, S2814A, and S2814D mouse ventricles identified 72 proteins, with 20 being high confidence RyR2 interactors. Of these, 14 had an increase in their binding to RyR2 S2814A but a decrease in their binding to RyR2 S2814D. We independently validated three protein hits, Idh3b, Aifm1, and Cpt1b, as RyR2 interactors by western blots and showed that Aifm1 and Idh3b had significantly decreased binding to RyR2 S2814D compared to WT and S2814A, consistent with MS findings. Conclusion: By applying state-of-the-art proteomic approaches, we discovered a number of novel RyR2 interactors in the mouse heart. In addition, we found and defined specific alterations in the RyR2 interactome that were dependent on the phosphorylation status of RyR2 at S2814. These findings yield mechanistic insights into RyR2 regulation which may guide future drug designs.

scholarly journals Transcriptome analysis identified long non-coding RNAs involved in the adaption of yak to high-altitude environments

2020 ◽  
Vol 7 (9) ◽  
pp. 200625
Author(s):  
Jin-Wei Xin ◽  
Zhi-Xin Chai ◽  
Cheng-Fu Zhang ◽  
Yu-Mei Yang ◽  
Qiang Zhang ◽  
...  
Keyword(s):  
Muscle Contraction ◽  
High Altitude ◽  
Target Genes ◽  
Calcium Release ◽  
Phosphoglycerate Mutase ◽  
Acid Oxidation ◽  
Transcriptional Level ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Kegg Pathways

The mechanisms underlying yak adaptation to high-altitude environments have been investigated using various methods, but no report has focused on long non-coding RNA (lncRNA). In the present study, lncRNAs were screened from the gluteus transcriptomes of yak and their transcriptional levels were compared with those in Sanjiang cattle, Holstein cattle and Tibetan cattle. The potential target genes of the differentially expressed lncRNAs between species/strains were predicted using cis and trans models. Based on cis -regulated target genes, no KEGG pathway was significantly enriched. Based on trans -regulated target genes, 11 KEGG pathways in relation to energy metabolism and three KEGG pathways associated with muscle contraction were significantly enriched. Compared with cattle strains, transcriptional levels of acyl-CoA dehydrogenase, acyl-CoA-binding protein, 3-hydroxyacyl-CoA dehydrogenase were relatively higher and those of glyceraldehyde 3-phosphate dehydrogenase, phosphoglycerate mutase 1, pyruvate kinase and lactate/malate dehydrogenase were relatively lower in yak, suggesting that yaks activated fatty acid oxidation but inhibited glucose oxidation and glycolysis. Besides, NADH dehydrogenase and ATP synthase showed lower transcriptional levels in yak than in cattle, which might protect muscle tissues from deterioration caused by reactive oxygen species (ROS). Compared with cattle strains, the higher transcriptional level of glyoxalase in yak might contribute to dicarbonyl stress resistance. Voltage-dependent calcium channel/calcium release channel showed a lower level in yak than in cattle strains, which could reduce the Ca 2+ influx and subsequently decrease the risk of hypertension. However, levels of EF-hand and myosin were higher in yak than in cattle strains, which might enhance the negative effects of reduced Ca 2+ on muscle contraction. Overall, the present study identified lncRNAs and proposed their potential regulatory functions in yak.

Sarcoplasmic reticulum calcium leak and cardiac arrhythmias

2007 ◽  
Vol 35 (5) ◽  
pp. 952-956 ◽  
Author(s):  
M.G. Chelu ◽  
X.H.T. Wehrens
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Arrhythmias ◽  
Ventricular Arrhythmias ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Incomplete Closure ◽  
Sarcoplasmic Reticulum Calcium

Ventricular arrhythmias deteriorating into sudden cardiac death are a major cause of mortality worldwide. The recent linkage of a genetic form of cardiac arrhythmia to mutations in the gene encoding RyR2 (ryanodine receptor 2) has uncovered an important role of this SR (sarcoplasmic reticulum) calcium release channel in triggering arrhythmias. Mutant RyR2 channels give rise to spontaneous release of calcium (Ca2+) from the SR during diastole, which enhances the probability of ventricular arrhythmias. Several molecular mechanisms have been proposed to explain the gain-of-function phenotype observed in mutant RyR2 channels. Despite considerable differences between the models discussed in the present review, each predicts spontaneous diastolic Ca2+ leak from the SR due to incomplete closure of the RyR2 channel. Enhanced SR Ca2+ leak is also observed in common structural diseases of the heart, such as heart failure. In heart failure, defective channel regulation in the absence of inherited mutations may also increase SR Ca2+ leak and initiate cardiac arrhythmias. Therefore inhibition of diastolic Ca2+ leak through SR Ca2+ release channels has emerged as a new and promising therapeutic target for cardiac arrhythmias.

scholarly journals Isolation and characterization of a gene for a ryanodine receptor/calcium release channel inDrosophila melanogaster

FEBS Letters ◽  
1994 ◽  
Vol 337 (1) ◽  
pp. 81-87 ◽  
Author(s):  
Hiroshi Takeshima ◽  
Miyuki Nishi ◽  
Naoyuki Iwabe ◽  
Takashi Miyata ◽  
Toshihiko Hosoya ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Calcium Release ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Isolation And Characterization

scholarly journals Unravelling calcium-release channel gating: clues from a hot disease

2004 ◽  
Vol 380 (1) ◽  
pp. e1-e3 ◽  
Author(s):  
Tommie V. McCARTHY ◽  
John J. MACKRILL
Keyword(s):  
Calcium Release ◽  
Distinct Point ◽  
Ryanodine Receptors ◽  
Point Mutations ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Present Evidence ◽  
Gating Mechanism ◽  
Biochemical Journal ◽  
Interdomain Interactions

Ryanodine receptors (RyRs) are a family of intracellular channels that mediate Ca2+ release from the endoplasmic and sarcoplasmic reticulum. More than 50 distinct point mutations in one member of this family, RyR1, cause malignant hyperthermia, a potentially lethal pharmacogenetic disorder of skeletal muscle. These mutations are not randomly distributed throughout the primary structure of RyR1, but are grouped in three discrete clusters. In this issue of the Biochemical Journal, Kobayashi et al. present evidence that interdomain interactions between two of these mutation-enriched regions play a key role in the gating mechanism of RyR1.

scholarly journals Protein Kinase A Phosphorylation of the Cardiac Calcium Release Channel (Ryanodine Receptor) in Normal and Failing Hearts

2002 ◽  
Vol 278 (1) ◽  
pp. 444-453 ◽  
Author(s):  
Steven Reiken ◽  
Marta Gaburjakova ◽  
Silvia Guatimosim ◽  
Ana M. Gomez ◽  
Jeanine D'Armiento ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Kinase A

scholarly journals Calcium channel ITPR2 and mitochondria–ER contacts promote cellular senescence and aging

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dorian V. Ziegler ◽  
David Vindrieux ◽  
Delphine Goehrig ◽  
Sara Jaber ◽  
Guillaume Collin ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Calcium Release ◽  
Liver Steatosis ◽  
Metabolic Stress ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Age Related ◽  
Trisphosphate Receptor

AbstractCellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.

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