scholarly journals Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3

2016 ◽  
Vol 114 (2) ◽  
pp. E228-E236 ◽  
Author(s):  
Jeremy W. Linsley ◽  
I-Uen Hsu ◽  
Linda Groom ◽  
Viktor Yarotskyy ◽  
Manuela Lavorato ◽  
...  
Keyword(s):  
Native American ◽  
Dynamic Imaging ◽  
Release Channel ◽  
Rich Domain ◽  
Dihydropyridine Receptors ◽  
Ec Coupling ◽  
Wide Range ◽  
Ryanodine Receptor 1 ◽  
Domain 3 ◽  
Cysteine Rich Domain

Skeletal muscle contractions are initiated by an increase in Ca2+ released during excitation–contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca2+ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native American myopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3NAM myofibers exhibited increased caffeine-induced Ca2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+ in internal stores, which is consistent with increased SR luminal Ca2+. These findings define critical roles for Stac3 in EC coupling and human disease.

Anaesthesia and neuromuscular disorders: what a neurologist needs to know

2020 ◽  
pp. practneurol-2020-002633
Author(s):  
Luuk R van den Bersselaar ◽  
Marc M J Snoeck ◽  
Madelief Gubbels ◽  
Sheila Riazi ◽  
Erik-Jan Kamsteeg ◽  
...  
Keyword(s):  
General Anaesthesia ◽  
Neuromuscular Disorders ◽  
Muscle Relaxants ◽  
Rich Domain ◽  
Specific Advice ◽  
Voltage Dependent ◽  
Life Threatening ◽  
Ryanodine Receptor 1 ◽  
Domain 3 ◽  
Cysteine Rich Domain

Neurologists are often asked for specific advice regarding patients with neuromuscular disease who require general anaesthesia. However, guidelines on specific neuromuscular disorders do not usually include specific guidelines or pragmatic advice regarding (regional and/or general) anaesthesia or procedural sedation. Furthermore, the medical literature on this subject is mostly limited to publications in anaesthesiology journals. We therefore summarise general recommendations and specific advice for anaesthesia in different neuromuscular disorders to provide a comprehensive and accessible overview of the knowledge on this topic essential for clinical neurologists. A preoperative multidisciplinary approach involving anaesthesiologists, cardiologists, chest physicians, surgeons and neurologists is crucial. Depolarising muscle relaxants (succinylcholine) should be avoided at all times. The dose of non-depolarising muscle relaxants must be reduced and their effect monitored. Patients with specific mutations in RYR1 (ryanodine receptor 1) and less frequently in CACNA1S (calcium channel, voltage-dependent, L type, alpha 1S subunit) and STAC3 (SH3 and cysteine rich domain 3) are at risk of developing a life-threatening malignant hyperthermia reaction.

scholarly journals Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain

2019 ◽  
Vol 5 (7) ◽  
pp. eaau4202 ◽  
Author(s):  
Janna M. Bigalke ◽  
Shintaro Aibara ◽  
Robert Roth ◽  
Göran Dahl ◽  
Euan Gordon ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Neurological Diseases ◽  
Receptor Activation ◽  
Loss Of Function ◽  
Calcium Binding Site ◽  
Signaling Complex ◽  
Rich Domain ◽  
Extracellular Region ◽  
Domain 3 ◽  
Cysteine Rich Domain

Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFRα2 and determined its structure at 5.7-Å resolution by cryo-EM. The proteins form an assembly through RET-GFRα2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFRα2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases.

scholarly journals Isometric training improves fatigue resistance in dystrophin-deficient muscle

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Nao Yamauchi ◽  
Iori Kimura ◽  
Yuki Ashida ◽  
Azuma Naito ◽  
Nao Tokuda ◽  
...  
Keyword(s):  
Fatigue Resistance ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Blue Dye ◽  
Rich Domain ◽  
Flexor Muscles ◽  
Domain 3 ◽  
Plantar Flexor Muscles ◽  
Cysteine Rich Domain

Eccentric contractions, in which the muscle is stretched during contraction, cause substantially greater damage than isometric (ISO) contractions, in which the length of the muscle does not change during contraction. Here, we tested the hypothesis that ISO training improves fatigue resistance in skeletal muscle from dystrophin-deficient mdx52 mice (15–22 wk old). ISO training (100 Hz stimulation frequency, 0.25-s contractions every 0.5 s, 6 sets of 60 contractions) was performed on the left plantar flexor muscles in vivo with supramaximal electrical stimulation every other day for 4 wk. Compared with the normal control muscle, resistance to fatigue was reduced in the nontrained muscle from mdx52 mice, which was accompanied by a reduction in citrate synthase activity and the LC3BII/I ratio and an increase in the phosphorylation levels of Akt Ser473 and the expression levels of p62. ISO training restored these alterations and markedly increased in vivo fatigue resistance and PGC-1α expression in mdx52 muscles. Moreover, an increased number of Evans Blue dye-positive fibers was significantly reduced by ISO training in mdx52 muscles. In contrast, ISO training did not restore a reduction in the amount of SH3 and cysteine-rich domain 3 in mdx muscles. Thus, our data suggest that mitochondrial function is impaired in dystrophin-deficient muscles, which is likely to be induced by the defective autophagy due to persistent activation of Akt. ISO training inhibits the aberrant activation of Akt presumably by up-regulating the PGC-1α expression, which results in improved mitochondrial function and thus fatigue resistance in dystrophin-deficient muscles.

scholarly journals The Evolution of the Scavenger Receptor Cysteine-Rich Domain of the Class A Scavenger Receptors

2015 ◽  
Vol 6 ◽  
Author(s):  
Nicholas V. L. Yap ◽  
Fiona J. Whelan ◽  
Dawn M. E. Bowdish ◽  
G. Brian Golding
Keyword(s):  
Scavenger Receptor ◽  
Scavenger Receptors ◽  
Class A ◽  
Rich Domain ◽  
Cysteine Rich Domain

scholarly journals The unusual structure of the PiggyMac cysteine-rich domain reveals zinc finger diversity in PiggyBac-related transposases

Mobile DNA ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marc Guérineau ◽  
Luiza Bessa ◽  
Séverine Moriau ◽  
Ewen Lescop ◽  
François Bontems ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Dna Cleavage ◽  
Trichoplusia Ni ◽  
Catalytic Domain ◽  
Structural Diversity ◽  
Paramecium Tetraurelia ◽  
Lysine Methylation ◽  
Unusual Structure ◽  
Rich Domain ◽  
Cysteine Rich Domain

Abstract Background Transposons are mobile genetic elements that colonize genomes and drive their plasticity in all organisms. DNA transposon-encoded transposases bind to the ends of their cognate transposons and catalyze their movement. In some cases, exaptation of transposon genes has allowed novel cellular functions to emerge. The PiggyMac (Pgm) endonuclease of the ciliate Paramecium tetraurelia is a domesticated transposase from the PiggyBac family. It carries a core catalytic domain typical of PiggyBac-related transposases and a short cysteine-rich domain (CRD), flanked by N- and C-terminal extensions. During sexual processes Pgm catalyzes programmed genome rearrangements (PGR) that eliminate ~ 30% of germline DNA from the somatic genome at each generation. How Pgm recognizes its DNA cleavage sites in chromatin is unclear and the structure-function relationships of its different domains have remained elusive. Results We provide insight into Pgm structure by determining the fold adopted by its CRD, an essential domain required for PGR. Using Nuclear Magnetic Resonance, we show that the Pgm CRD binds two Zn2+ ions and forms an unusual binuclear cross-brace zinc finger, with a circularly permutated treble-clef fold flanked by two flexible arms. The Pgm CRD structure clearly differs from that of several other PiggyBac-related transposases, among which is the well-studied PB transposase from Trichoplusia ni. Instead, the arrangement of cysteines and histidines in the primary sequence of the Pgm CRD resembles that of active transposases from piggyBac-like elements found in other species and of human PiggyBac-derived domesticated transposases. We show that, unlike the PB CRD, the Pgm CRD does not bind DNA. Instead, it interacts weakly with the N-terminus of histone H3, whatever its lysine methylation state. Conclusions The present study points to the structural diversity of the CRD among transposases from the PiggyBac family and their domesticated derivatives, and highlights the diverse interactions this domain may establish with chromatin, from sequence-specific DNA binding to contacts with histone tails. Our data suggest that the Pgm CRD fold, whose unusual arrangement of cysteines and histidines is found in all PiggyBac-related domesticated transposases from Paramecium and Tetrahymena, was already present in the ancestral active transposase that gave rise to ciliate domesticated proteins.

scholarly journals Elucidation of Binding Determinants and Functional Consequences of Ras/Raf-Cysteine-rich Domain Interactions

2000 ◽  
Vol 275 (29) ◽  
pp. 22172-22179 ◽  
Author(s):  
Jason G. Williams ◽  
Jonelle K. Drugan ◽  
Gwan-Su Yi ◽  
Geoffrey J. Clark ◽  
Channing J. Der ◽  
...  
Keyword(s):  
Rich Domain ◽  
Domain Interactions ◽  
Functional Consequences ◽  
Binding Determinants ◽  
Cysteine Rich Domain

Prevention of Alcohol Misuse: A Review of Health Promotion Efforts among American Indians

1995 ◽  
Vol 9 (4) ◽  
pp. 288-299 ◽  
Author(s):  
Philip A. May ◽  
James R. Moran
Keyword(s):  
Health Promotion ◽  
Native American ◽  
American Indian ◽  
American Indians ◽  
Local Community ◽  
Alcohol Misuse ◽  
Heavy Drinking ◽  
Community Empowerment ◽  
Negative Consequences ◽  
Wide Range

Purpose. The purpose of this review is to provide an overview of a wide range of potentially useful strategies to address the prevention of alcohol misuse among American Indians. This broad approach to the review is useful because the extreme heterogeneity of the American Indian population requires that health promotion professionals explore many options and tailor their activities to specific communities. Search Method. A literature search was initiated through MEDLINE using the following key words: prevention, alcohol, substance abuse, American Indian, and Native American. The search yielded 29 articles from the years 1982 through 1994. These articles, along with 45 previously identified in three overview articles, form the basis of the review and discussion in this paper. Summary of findings. As a group, American Indians experience many health problems that are related to alcohol misuse. Comparison of Indians to non-Indians shows that the age of first involvement with alcohol is younger, the frequency and amount of drinking is greater, and negative consequences are more common. Health promotion programs that address these issues must take into account American Indian heterogeneity and should use a comprehensive approach that addresses both heavy drinking and the sequelae of problems related to alcohol misuse. Major Conclusions. Important concepts for providing health promotion services to this population are: cultural relevance must be carefully planned and monitored; individuals in the local community must be involved; the drunken Indian stereotype must be addressed; and community empowerment should be an important goal.

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