更新于：2024-11-01

RYR3

更新于：2024-11-01

基本信息

别名

Brain ryanodine receptor-calcium release channel、Brain-type ryanodine receptor、HBRR

+ [4]

简介

Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction. May regulate Ca(2+) release by other calcium channels. Calcium channel that mediates Ca(2+)-induced Ca(2+) release from the endoplasmic reticulum in non-muscle cells. Contributes to cellular calcium ion homeostasis (By similarity). Plays a role in cellular calcium signaling.

关联

项与 RYR3 相关的药物

M-201

靶点

RYR1 x RYR2 x RYR3

作用机制

RYR1调节剂 [+2]

在研机构

AETAS Pharma Co., Ltd.

原研机构

AETAS Pharma Co., Ltd.

在研适应症

心脏衰竭

非在研适应症

心房颤动

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

Alzheimer's disease (Miramoon Pharma)

靶点

RYR1 x RYR2 x RYR3

作用机制

RYR1调节剂 [+2]

在研机构

Miramoon Pharma SL

原研机构

Miramoon Pharma SL

在研适应症

阿尔茨海默症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 RYR3 相关的临床试验

NCT04464681 / Completed临床1期IIT

A Randomized, Double-Blind, Placebo-Controlled, Multiple Continuous Intravenous Injection, Dose Escalation, Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of M201-A in Healthy Japanese Subjects

This Phase I is designed to evaluate the safety, tolerability and pharmacokinetics of multiple ascending doses of M201-A administered by multiple continuous intravenous injection in Healthy Japanese subjects.

开始日期2020-03-30

申办/合作机构

Kitasato University

[+1]

NCT04609059 / Unknown status临床2期IIT

First-in-Patient Study for Sing le Dose of M201-A Hydrochloride Injection in Japanese Patients With Paroxysmal Atrial Fibrillation

First-in-Patient Study for sing le dose of M201-A hydrochloride injection in Japanese patients with paroxysmal atrial fibrillation.

开始日期2019-05-07

申办/合作机构

Kitasato University

[+1]

NCT03055403 / Completed临床1期IIT

A Randomized, Double-Blind, Placebo-Controlled, Single Continuous Intravenous Injection, Dose Escalation, Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of M201-A in Healthy Japanese Subjects

This Phase I first-in-human is designed to evaluate the safety, tolerability and pharmacokinetics of single ascending doses of M201-A administered by single continuous intravenous injection in Healthy Japanese subjects.

开始日期2017-02-17

申办/合作机构

Kitasato University

[+1]

100 项与 RYR3 相关的临床结果

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100 项与 RYR3 相关的转化医学

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0 项与 RYR3 相关的专利（医药）

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524

项与 RYR3 相关的文献（医药）

2024-09-01·American Journal of Physiology-Cell Physiology

Purinergic agonists increase [Ca²⁺]_i in rat conjunctival goblet cells through ryanodine receptor type 3

Article

作者: Yang, Menglu ; Utheim, Tor P. ; Lee, Changrim ; Bair, Jeffrey ; Dartt, Darlene ; Reiten, Ole K. ; Fjaervoll, Haakon K. ; Fjaervoll, Ketil A.

ATP and benzoylbenzoyl-ATP (BzATP) induce mucin secretion through an increase in free cytosolic calcium concentration ([Ca2+]i) in conjunctival goblet cells (CGCs). The mechanisms through which ATP and BzATP increase [Ca2+]i in CGCs are unclear. Ryanodine receptors (RyRs) are fundamental in [Ca2+]i regulation in excitable cells. Herein, we find that ATP and BzATP increase [Ca2+]i through the activation of protein kinase A, voltage-gated calcium channels, and RyRs, and that RyRs are crucial for nonexcitable CGCs’ Ca2+i homeostasis.

2024-08-01·British Journal of Pharmacology

Differential contributions of G protein‐ or arrestin subtype‐mediated signalling underlie urocortin 3‐induced somatostatin secretion in pancreatic δ cells

Article

作者: Xiao, Peng ; Ning, Shang-Lei ; Wang, Jin ; Lin, Jing-Yu ; Fang, Le ; Pan, Wei ; Cheng, Jie ; Yang, Fan ; Yu, Xiao ; Wang, Kai-Yu ; Qi, Hai-Bo ; Cheng, Qiu-Xia ; Gao, Ming-Xin ; Sun, Jin-Peng ; An, Wen-Tao

AbstractBackground and PurposePancreatic islets are modulated by cross‐talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic β cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis.Experimental ApproachHere, we used Arrb1−/−, Arrb2−/−, Gsfl/fl and Gqfl/fl knockout mice, the G11‐shRNA‐GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and β‐arrestin1 to CRF2R contributed to UCN3‐induced SST secretion in pancreatic δ cells.Key ResultsOur study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs‐mediated UCN3‐ CRF2R axis for SST secretion, the interaction of SYT1 with β‐arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors.Conclusions and ImplicationsCollectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3‐ CRF2R signalling in pancreatic β‐δ‐cell circuits, which may facilitate the understanding of fine‐tuned glucose homeostasis networks.

2024-06-01·The Pharmacogenomics Journal

Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone

Article

作者: Pilling, Luke C ; Bowden, Jack ; Masoli, Jane A H ; Melzer, David ; Türkmen, Deniz ; Kuo, Chia-Ling ; Delgado, João

AbstractPharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10−5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.

项与 RYR3 相关的新闻（医药）

2023-07-17

·生物谷

《自然·神经科学》：破解心衰伤脑之迷！哥伦比亚大学团队发现心力衰竭诱导认知障碍的机制

心力衰竭患者往往会出现认知障碍，这并非巧合。在这项研究中，Andrew R. Marks和他的同事们揭示心力衰竭引发认知障碍的机制，并使用用于治疗心脏疾病的实验药物，成功提高了心力衰竭小鼠的认知能力。一旦心脏无法正常地将血液泵送到身体的其它部位，大脑会发生什么变化？心源性痴呆症（cardiogenic dementia），这个概念最早于1977年出现在《柳叶刀》期刊上，便是指与心力衰竭相关的认知功能下降[1]。临床数据显示，20%-80%的心力衰竭患者遭受心源性痴呆的困扰，表现为健忘或学习能力较差，可能不利于患者的自我护理或遵行医嘱，甚至干扰患者对于心力衰竭病情恶化的感知和描述。而近年来，越来越多的证据支持，在这层关系中，心力衰竭属于“始作俑者”，可能对大脑产生负面影响、导致认知功能下降。如今，心力衰竭已经成为全球范围内患者人数增长最为迅速的一种心血管疾病，影响着数百万人。破解心力衰竭与认知障碍之间的谜题，成为众多科学家们的目标。美国哥伦比亚大学的Andrew R. Marks和他的同事们发现，心力衰竭会导致大脑神经元中的内质网钙离子泄漏，引发神经传递通路紊乱、多种酶激活等，从而导致认知能力下降。使用药物修复神经元的钙离子释放通道、阻止钙离子异常泄露，则可以改善心力衰竭小鼠的认知能力[2]。文章于近日发表在Nature Neuroscience期刊上。论文首页截图钙离子是重要的信号分子，其细胞内的平衡受钙离子释放通道蛋白RyR调节。响应细胞内信号分子后，RyR通道打开，将储存在内质网中的钙离子释放，短时间内迅速提高细胞质中钙离子水平、放大钙信号，从而触发一系列细胞功能和生理过程。在心力衰竭的早期阶段，心肌细胞中的RyR通道无法正常关闭，这导致过多的钙离子泄漏，削弱心肌细胞的收缩能力，造成心脏损伤。除了心肌细胞，RyR通道还广泛存在于平滑肌细胞、神经元等许多类型细胞中，并分为RyR1、RyR2、RyR3三个亚型。在这项研究中，Andrew R. Marks 和他的同事们打算前往大脑看看神经元中的RYR通道到底是怎么回事。为此，研究者们获取9名心力衰竭患者和4名非心力衰竭人员（对照组）的大脑海马组织样本进行分析。结果显示，与对照组相比，心力衰竭患者的大脑神经元RyR通道表现出异常特征，包括过度磷酸化、半胱氨酸亚硝酰化、缺乏维持构象稳定的亚基等。同时观察到，心力衰竭患者的大脑神经元RyR通道开放概率增加、开放时间延长、闭合时间缩短，且存在钙离子从内质网异常泄漏到细胞质的情况。如此来看，对于心力衰竭患者来说，心脏和大脑中负责调控钙离子的通道都出现异常，心肌细胞和神经元中的钙离子水平失衡。心力衰竭患者的海马神经元出现钙离子泄露由于患者的临床表现很复杂，接下来研究者们改用小鼠进行实验，探索与心力衰竭相关的认知障碍——心源性痴呆症究竟是如何发生的。与患者样本的分析结果一致，心力衰竭小鼠的大脑神经元RyR通道表现出同样的异常特征并伴随内质网钙离子泄露。开放场实验、高架十字迷宫实验、水迷宫实验等测试结果则显示，心力衰竭小鼠表现出异常行为和记忆缺陷，包括探索行为、短期记忆和空间学习记忆的下降。从大脑的功能和能量代谢来看，心力衰竭小鼠的长时程增强作用（LTP）受到损害，即神经元之间传递信号的强度和持久性减弱，以及葡萄糖代谢受损（这是阿尔茨海默病诊断的临床标志）。水迷宫测试结果显示，心力衰竭小鼠表现出长期学习和记忆能力下降然而，堵住这个溃堤的大坝，一切都可以得到逆转。 Rycal药物是RyR通道的稳定剂，通过稳定RyR通道的构象，阻止其过度开放或渗漏钙离子，从而保持细胞内钙离子的正常平衡状态。目前，Rycal药物已被广泛用于与钙离子泄露相关疾病的临床试验，比如心脏疾病或其它肌肉疾病。在这里，研究者们使用了一种称为S107的Rycal药物，S107能够穿过血脑屏障。心力衰竭小鼠接受S107治疗后，大脑神经元RyR通道的结构和功能被修复，内质网钙离子泄露现象减少。更重要的是，这些小鼠的认知功能得到改善，神经元之间的通信和突触传递得到改善，并维持正常的大脑代谢活动。不仅如此，研究者们还采用了另一种Rycal药物进行对比。与S107不同，ARM036虽然也能修复RyR通道，但无法穿过血脑屏障。结果显示，ARM036治疗未能改善心力衰竭小鼠的认知功能。除了负责稳定通道构象的Rycal药物，非选择性β-肾上腺素受体拮抗剂普萘洛尔、TGF-β抑制剂SD-208以不同的机制在调节RyR通道、恢复钙离子平衡以及改善心脏结构和功能方面发挥作用。同样地，这两种药物的治疗帮助心力衰竭小鼠的大脑神经元RyR恢复常态，改善认知障碍。针对RyR通道的不同药物治疗，心力衰竭小鼠的认知能力改变随后，研究者们利用遗传学技术构建不同突变体的小鼠模型，验证大脑神经元的RyR通道异常、内质网钙离子泄露对认知功能的负面影响，并指出针对RyR通道进行干预可能有助于改善认知功能。他们进一步对其中的机制进行探索。结果显示，当心力衰竭发生时，肾上腺素途径的激活，正是导致神经元中受RyR通道调控的钙离子发生泄漏的原因。神经元中的内质网钙离子泄露后，神经递质异常释放、炎症反应增加，神经元线粒体功能紊乱、发生氧化应激反应。另外，钙离子泄露还会导致几种关键酶的活化（如AMPK、CDK5、CaMKII），这些酶的激活是阿尔茨海默病大脑中Tau蛋白和淀粉样沉积形成的触发因素。好看的机制图总而言之，心力衰竭患者往往会出现认知障碍，这并非巧合。在这项研究中，Andrew R. Marks和他的同事们揭示心力衰竭引发认知障碍的机制，并使用用于治疗心脏疾病的实验药物，成功提高了心力衰竭小鼠的认知能力。