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Roles of Calsequestrin in the Control of Calcium Signals in Health and Disease

Calsequestrin 在控制健康和疾病钙信号中的作用

基本信息

批准号：
9291875
负责人：
CHULHEE KANG
金额：
$ 1.46万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9291875
关键词：
Address Adult Affinity Anabolism Applied Skills Basic Science Binding Buffers Calcium Calcium Binding Calcium Signaling Calsequestrin Canada Cardiac Catecholaminergic Polymorphic Ventricular Tachycardia Cell physiology Cells Clinical Complex Computer Simulation Dependence Deposition Diagnosis Diffusion Disease Failure Fiber Foundations Frequencies Functional disorder Future Goals Health Heart Diseases Hepatocyte Homologous Gene Human Image In Vitro Individual Ions Knockout Mice Lead Life Link Malignant hyperpyrexia due to anesthesia Measurement Measures Mechanics Mediating Modification Molecular Movement Mus Muscle Mutate Mutation Myocardium Neurons Null Lymphocytes Oligopeptides Outcome Patients Permeability Phenotype Physical Chemistry Polymers Property Protein Isoforms Proteins Proteolysis Public Health Recombinants Resources Retrieval Rewards Role Signal Transduction Signaling Molecule Skeletal Muscle Specific qualifier value Staging Stretching Striated Muscles Structure Structure-Activity Relationship Techniques Testing Tissues Translating Triad Acrylic Resin Variant Work design disease phenotype functional gain functional loss functional restoration human disease human subject in vitro testing in vivo mutant operation polymerization prevent research study skeletal stem triadin vector

项目摘要

Intracellular Ca signals reach their greatest intensity and highest frequencies in striated muscle. Sustaining them is calsequestrin, Casq, notable for its high Ca-binding capacity, convenient affinity and for two unique properties demonstrated in vitro: a marked dependence of its ability to bind Ca on how much free Ca is present and a Ca-driven tendency to polymerize. In addition to these Ca storing properties, there are evidences for a “gating” function, whereby Casq senses the surrounding Ca concentration and accordingly induces the Ca release channel, RyR, to open or close, through a mechanical link presumably provided by triadin, Tr. The relevance of these functions becomes obvious in view of multiple mutations in Casq that are linked to grave diseases. Our goal is to define the operation in vivo of these unique properties demonstrated in vitro. To this end we joined a lab that has driven the study of Casq's physical chemistry and one that pioneered the quantification of Casq's functions in adult muscle. The plan includes the testing, in vitro and in vivo, of three hypotheses: (1) the extent and type of polymerization of Casq in cells changes as [Ca] depletes inside the cellular store (SR). (2) Changes in [Ca2+]SR are translated, via Casq and Tr, to gating changes in the RyR. (3) Mutations in Casq2 linked to the disease CPVT (catecholaminergic polymorphic ventricular tachycardia), as well as M87T, a variant in Casq1 present in a sizable percentage of patients tested for the disease MH (malignant hyperthermia), cause the disease phenotype through mechanisms (1) and (2). To test (1) we will examine the EM structure of Casq1 in Ca-depleted cells, test the ability of a non-polymerizing mutated Casq1 to restore function in Casq-null cells, and carry out in vitro measurements of isotopic Ca diffusion, probing whether the presence of Casq alters Ca diffusion, and how the effects depends on Casq polymerization. For (2) we will explore the effects on Ca signaling of eliminating the putative link provided by Tr in (a) Tr-null mice and (b) cells acutely deprived of the link by expression of “decoys”, the oligopeptides that bind Casq in the Tr sequence. For (3) we will characterize the Ca-dependent physical chemistry of 11 known mutants of Casq2, the homologous mutants of Casq1 and its M87T variant. We will then test the ability of these mutants to restore function in Casq-null mouse fibers. While understanding how this iconic biobuffer works will be a main reward, the long-term goal is to build a basic science foundation translatable to rational strategies that address human diseases, namely: find the causative mutationgenerate the proteincharacterize its function in vitro  then in vivo specify the pathogenic functional gain or loss. Successful completion of these stages will allow us in future iterations of the project to design possible rescue strategiestest their efficacy.

细胞内钙离子信号在横纹肌中达到最大强度和最高频率。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Perspectives on "Control of Ca release from within the cardiac sarcoplasmic reticulum".

DOI：
10.1085/jgp.201711847
发表时间：
2017-09-04
期刊：
The Journal of general physiology
影响因子：
0
作者：
Ríos E
通讯作者：
Ríos E

A better method to measure total calcium in biological samples yields immediate payoffs.

DOI：
10.1085/jgp.201511370
发表时间：
2015-03
期刊：
The Journal of general physiology
影响因子：
0
作者：
Manno C;Ríos E
通讯作者：
Ríos E

Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation.

DOI：
10.7554/elife.78874
发表时间：
2023-02-01
期刊：
eLife
影响因子：
7.7
作者：
Tammineni ER;Figueroa L;Manno C;Varma D;Kraeva N;Ibarra CA;Klip A;Riazi S;Rios E
通讯作者：
Rios E

Characterization of Post-Translational Modifications to Calsequestrins of Cardiac and Skeletal Muscle.

DOI：
10.3390/ijms17091539
发表时间：
2016-09-13
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Lewis KM;Munske GR;Byrd SS;Kang J;Cho HJ;Ríos E;Kang C
通讯作者：
Kang C

Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes.

细胞内钙泄漏会降低人体肌肉中的葡萄糖储存，促进高血糖和糖尿病。

DOI：
10.7554/elife.53999
发表时间：
2020
期刊：
eLife
影响因子：
7.7
作者：
Tammineni,EshwarR;Kraeva,Natalia;Figueroa,Lourdes;Manno,Carlo;Ibarra,CarlosA;Klip,Amira;Riazi,Sheila;Rios,Eduardo
通讯作者：
Rios,Eduardo