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Carbohydrate storage in cells: a laboratory activity for the assessment of glycogen stores in biological tissues. 细胞中的碳水化合物储存:评估生物组织中糖原储存的实验室活动。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-07-11 DOI: 10.1152/advan.00023.2024
Guilherme Brito-da-Silva, Gustavo Manzanares, Beatriz Beltrame Barone, Vanessa Silva Dos Santos, Sabrina Sturion Fillipini, Paulo G Gandra

Carbohydrates and fats constitute our primary energy sources. The importance of each of these energy substrates varies across cell types and physiological conditions. For example, the brain normally relies almost exclusively on glucose oxidation, whereas skeletal muscle shifts from lipids toward higher carbohydrate oxidation rates as exercise intensity increases. Understanding how carbohydrates are stored in our cells and which tissues contain significant carbohydrate stores is crucial for health professionals, especially given the role of carbohydrate metabolism in various pathophysiological conditions. This laboratory activity uses a simple and low-cost iodine binding method to quantify glycogen in mouse skeletal muscle and liver samples. By integrating the results of this activity with literature data, students can determine overall glycogen storage in the human body. The primary goal of the activity is to enhance students' understanding of the importance and limitations of glycogen stores in energy metabolism.NEW & NOTEWORTHY Carbohydrates are one of the primary energy sources utilized by our cells. Liver and skeletal muscle glycogen, which are the main carbohydrate reserves in the body, play a central role in energy metabolism, especially during periods of fasting and exercise. In this laboratory activity, students measure glycogen levels in tissues to gain insights into how carbohydrates are stored in our cells and understand the role and limitations of liver and muscle carbohydrate stores.

碳水化合物和脂肪是我们的主要能量来源。在不同的细胞类型和生理条件下,这两种能量底物的重要性各不相同。例如,大脑通常几乎完全依赖葡萄糖氧化,而骨骼肌则随着运动强度的增加,从脂类转向更高的碳水化合物氧化率。了解碳水化合物如何储存在我们的细胞中,以及哪些组织含有大量的碳水化合物储存,对于健康专业人员来说至关重要,尤其是考虑到碳水化合物代谢在各种病理生理状况中的作用。本实验活动使用一种简单、低成本的碘结合方法来量化小鼠骨骼肌和肝脏样本中的糖原。通过将该活动的结果与文献数据相结合,学生可以确定人体内糖原的总体储存情况。这项活动的主要目的是加深学生对糖原储存在能量代谢中的重要性和局限性的理解。
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引用次数: 0
Hans Berger (1873-1941): the German psychiatrist who recorded the first electrical brain signal in humans 100 years ago. 汉斯-伯格(1873-1941 年):德国精神病学家,100 年前首次记录了人类脑电信号。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-09-05 DOI: 10.1152/advan.00119.2024
Alberto Arturo Vergani

In 1924, at the University Hospital of Jena, Hans Berger first recorded an electrical brain signal in humans. This discovery revolutionized clinical neuroscience and neurotechnology, as it contributed to both electrophysiology and the development of the electroencephalogram (EEG). This article provides a historical overview of Hans Berger's seminal contributions, highlighting the importance of his early recordings, the motivations that drove him, and the scientific problems he had to initiate and solve, in a historical context of profoundly changing circumstances. He also faced low acceptance of his works initially, and only belatedly did they become accepted by the scientific community. Berger was known to be a humble but tenacious person who believed in his convictions to the core, and this strength of will is an example of passion for students and scholars of neuroscience.NEW & NOTEWORTHY In 1924, at the University Hospital in Jena, Hans Berger first recorded human brain electrical signals, revolutionizing clinical neurophysiology and neurotechnology. He developed the electroencephalogram (EEG) and identified alpha waves in the human scalp. Although initially met with skepticism, his work was later recognized as fundamental. Berger's perseverance and conviction in his research serve as an inspiring example of dedication for students and scientists in neuroscience.

1924 年,汉斯-伯杰在耶拿大学医院首次记录到人类的脑电信号。这一发现彻底改变了临床神经科学和神经技术,促进了电生理学和脑电图(EEG)的发展。手稿对汉斯-伯杰的开创性贡献进行了历史性概述,强调了他早期记录的重要性、推动他前进的动力,以及他在环境发生深刻变化的历史背景下提出和解决的科学问题。他的作品最初也面临着接受度低的问题,直到后来才被科学界所接受。众所周知,伯杰是一个谦逊而顽强的人,他对自己的信念坚信不疑,这种坚强的意志力是神经科学学生和学者们学习的榜样。
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引用次数: 0
Using systems modeling to facilitate undergraduate physiology student learning and retention of difficult concepts. 利用系统建模促进生理学本科生学习和保留难懂的概念。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-08-29 DOI: 10.1152/advan.00020.2024
Michelle Pauley Murphy, Woei Hung

Physiology concepts, such as acid-base balance, may be difficult for students to understand. Systems modeling, a cognitive tool, allows students to visualize their mental model of the problem space to enhance learning and retention. We performed a within-subjects three-period randomized control comparison of systems modeling versus written discussion activities in an undergraduate asynchronous online Anatomy and Physiology II course. Participants (n = 108) were randomized to groups with differing treatment orders across three course units: endocrine, immune, and acid-base balance. Participants demonstrated content understanding through either constructing systems modeling diagrams (M) or written discussion posts (W) in a MWM, MMW, or WMM sequence. For each of three units, student performance was assessed on 6 standardized multiple-choice questions embedded within a 45-question exam. The same 6 questions per unit, 18 questions in total, were again assessed on the 75-question final exam. The groups demonstrated no significant difference in performance in the endocrine unit exam [mean difference (MD) = -0.036]. However, the modeling group outperformed the writing group in the immune unit exam (MD = 0.209) and widened the gap in the acid-base balance unit exam (MD = 0.243). On the final exam, performance was again higher for the modeling group on acid-base balance content, as mean difference increased to 0.306 despite the final exam content for acid-base balance being significantly more difficult compared to other units [modeling: F(2) = 29.882, P < 0.001; writing: F(2) = 25.450, P < 0.001]. These results provide initial evidence that participation in systems modeling activities may enhance student learning of difficult physiology content as evidenced by improved multiple-choice question performance.NEW & NOTEWORTHY Physiology educators often intuitively utilize systems thinking and modeling while teaching difficult concepts. Guiding students in development of their own systems modeling skills by enhancing their visualization of their mental model of the problem space may improve performance on multiple-choice test questions.

学生可能难以理解酸碱平衡等生理学概念。系统建模作为一种认知工具,可以让学生将问题空间的心智模型可视化,从而提高学习效果和记忆力。研究方法我们在本科生异步在线《解剖生理学 II》课程中进行了系统建模与书面讨论活动的三期随机对照比较。参与者(n=108)被随机分配到三个课程单元(内分泌、免疫和酸碱平衡)中不同处理顺序的小组。学员通过构建系统建模图(M)或书面讨论帖(W),以MWM、MMW或WMM顺序展示对内容的理解。结果:在三个单元中的每一个单元,学生的成绩都是通过包含在 45 道题的考试中的六道标准化选择题来评估的。在 75 题的期末考试中,再次对每个单元的六道题(共 18 道题)进行评估。在内分泌单元考试中,两组成绩无明显差异(平均差异,MD=-0.036)。然而,建模组在免疫单元考试中的成绩超过了写作组(MD=0.209),并在酸碱平衡单元考试中拉大了差距(MD=0.243)。在期末考试中,尽管酸碱平衡的期末考试内容与其他单元相比明显更难,但建模组在酸碱平衡内容上的成绩再次高于写作组,平均分差距增至 0.306(建模组:F(2)=29.8;写作组:F(2)=29.8):F(2)=29.882, p结论:这些结果提供了初步证据,证明参与系统建模活动能提高学生对生理学难点内容的学习效果,这体现在选择题成绩的提高上。
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引用次数: 0
11th Annual Michigan Physiological Society Meeting: June 24-25, 2024. 第 11 届密歇根生理学会年会:2024 年 6 月 24-25 日。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 DOI: 10.1152/advan.00167.2024
Brianna D Harfmann, Subha Bhaskaran, John Zubek, Kevin Gordish, Andrew Butcko, Ruijie Liu, Jennifer R Vranish, Juli Della-Moretta, Christopher M Westercamp, Charles S Chung, Steven J Elmer
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引用次数: 0
Beyond the boards: too much time in study hall, too little societal impact. 超越黑板:自习时间太多,社会影响太小。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-08-08 DOI: 10.1152/advan.00148.2024
Heidi L Lujan, Stephen E DiCarlo
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引用次数: 0
The Diamond Framework for team-based active learning for physiology courses. 生理学课程团队主动学习的钻石框架。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-08-08 DOI: 10.1152/advan.00066.2023
Daniela G L Terson de Paleville, Staci W Saner

Benjamin Bloom published his Taxonomy of Educational Objectives: Handbook I: Cognitive Domain in 1956 (New York: David McKay, Co.) to help educators develop learning objectives for teaching. Several modifications have been made since then to adapt Bloom's taxonomy to various uses and disciplines (Crowe A, Dirks C, Wenderoth MP. CBE Life Sci Educ 7: 368-381, 2008; Orgill BD, Nolin J. StatPearls. Treasure Island, FL: StatPearls Publishing, 2023; Thompson AR, O'Loughlin VD. Anat Sci Educ 8: 493-501, 2015). In terms of the "Introduction of the Idea," as social constructivist educators, the authors of this article felt the need to adjust Bloom's taxonomy to match the unique characteristics of team-based learning (TBL) in physiology courses. In terms of "Outcomes," we are introducing the use of TBL for teaching physiology in undergraduate and graduate physiology courses that could be easily translated into other disciplines. Additionally, we are introducing the Diamond Framework for TBL, a modified Bloom's taxonomy to match the unique characteristics of TBL and to guide the writing of measurable learning outcomes and assignments.NEW & NOTEWORTHY Team-based learning (TBL) has gained popularity as an educational framework that facilitates teaching conceptual and procedural subjects. However, this technique is less popular among physiology and biomedical sciences. Here, we describe a step-by-step guide for incorporating this learning approach for physiology. Further, we created the Diamond Framework for TBL, a visual taxonomy inspired by Bloom's taxonomy, designed explicitly for TBL, in which the "application" component is at the core of the diamond.

本杰明-布鲁姆(Benjamin Bloom)于 1956 年出版了《教育目标分类学》[1],以帮助教育工作者制定教学学习目标。从那时起,人们对布鲁姆的分类法进行了多次修改,使其适用于各种用途和学科[2-4]。引入理念:作为社会建构主义教育者,本文作者认为有必要调整布卢姆分类法,以适应生理学课程中团队学习(TBL)的独特特点。成果:在此,我们介绍了在生理学本科课程中使用 TBL 教学法进行生理学教学的方法,这种方法可以很容易地应用到其他学科中。此外,我们还介绍了 TBL 的钻石框架(Diamond Framework for TBL),这是一种经过修改的布鲁姆分类法,用于指导撰写可衡量的学习成果和创建作业,以帮助学生应用新知识和技能。
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引用次数: 0
Visualizing filtration: a hands-on model for understanding Starling forces in glomerular filtration rate. 可视化滤过:了解肾小球滤过率中斯塔林力的动手模型。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-07-25 DOI: 10.1152/advan.00120.2024
Derek E Bowman, Heidi L Lujan, Stephen E DiCarlo

Understanding complex physiological processes is a cornerstone of medical education, and one such fundamental concept is the regulation of the glomerular filtration rate (GFR) by Starling forces. Therefore, developing a physiologically sound educational model to demonstrate these forces can significantly enhance the learning experience for students, providing them with a clear and comprehensive understanding of renal filtration. Starling forces include the glomerular capillary hydrostatic pressure, which drives plasma filtration; the plasma colloid osmotic pressure (also referred to as the oncotic pressure within the capillary), which opposes filtration; and the Bowman's capsule hydrostatic pressure, which resists fluid influx. Bowman's capsule oncotic pressure is typically considered negligible in healthy kidneys and, therefore, does not usually influence the glomerular filtration process. It is crucial for future clinicians to understand these Starling forces in order to monitor and manage kidney function effectively. To aid in understanding these concepts, we present a simple yet effective physical model of GFR. This model uses pressurized air and a serological pipette setup to simulate the filtration process, with a ping-pong ball's height representing GFR. Various perturbations demonstrate changes in Starling forces, allowing students to visualize the impact of different physiological and pathological conditions on GFR. This hands-on approach aims to simplify the complex interplay of factors affecting GFR, making it an invaluable educational tool for medical students.NEW & NOTEWORTHY Physical models enhance the understanding of complex physiological concepts. This Illumination introduces a hands-on model using pressurized air and a serological pipette to simulate glomerular filtration rate (GFR), with a ping-pong ball indicating filtration rate. The model demonstrates how Starling forces, glomerular capillary hydrostatic pressure, plasma colloid osmotic pressure, Bowman's capsule oncotic pressure, and Bowman's capsule hydrostatic pressure, affect GFR, providing a clear and comprehensive learning experience for students.

理解复杂的生理过程是医学教育的基石,其中一个基本概念就是斯特林力对肾小球滤过率(GFR)的调节。因此,开发一个生理学上合理的教学模型来演示这些作用力,可以大大增强学生的学习体验,让他们对肾脏滤过有一个清晰而全面的了解。斯特林力包括推动血浆滤过的肾小球毛细血管静水压、反对滤过的血浆胶体渗透压(也称为毛细血管内的渗透压)以及阻止液体流入的鲍曼囊静水压。在健康肾脏中,鲍曼囊膜张压力通常可以忽略不计,因此通常不会影响肾小球滤过过程。对于未来的临床医生来说,了解这些斯特林力对于有效监测和管理肾功能至关重要。为了帮助理解这些概念,我们提出了一个简单而有效的 GFR 物理模型。该模型使用加压空气和血清学吸管装置来模拟过滤过程,乒乓球的高度代表 GFR。各种扰动会显示斯特林力的变化,让学生直观地了解不同生理和病理条件对 GFR 的影响。这种动手操作的方法旨在简化影响肾小球滤过率的各种因素之间复杂的相互作用,使其成为医科学生宝贵的教育工具。
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引用次数: 0
Play your way to an "A": helping students engage during the social isolation of remote learning. 玩出你的 "A":在远程学习的社会隔离期帮助学生参与其中。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-08-08 DOI: 10.1152/advan.00052.2024
Robert E Brainard, Amy L Shaffer, Lewis J Watson, Daniela G L Terson de Paleville, Jeff C Falcone

With the increased attention focused on active learning, educators strive to find better and more innovative ways to engage students in the classroom. One of the hurtles that educators are presented with is that the classroom is no longer limited to a physical location but rather students and professor can meet via the internet, Before COVID-19, distance or remote learning was something that students, by and large, had the option of choosing in which whether to engage. Students had the option to take "online courses," whether those be synchronous remote learning or asynchronous online courses. Indeed, numerous studies have focused on investigating the efficacy of many different approaches to distance and online learning. Unfortunately, COVID 19 mandated a rapid transition to remote learning, and with this forced change has come what some students describe as "Zoom fatigue" (Wolf CR. Psychology Today, May 2020). Many students reported feeling exhausted, overwhelmed, and disengaged by the dramatic increase in mandated distance education required by the COVID pandemic. Video conferencing has become the "go-to" panacea for education during this time, and students are spending unprecedented amounts of time in front of a screen when normally they would be in a classroom. This heretofore singular and unique approach to education coupled with decreased peer-to-peer interaction has caused a problem with student engagement (Goodman BE, Barker MK, Cooke JE. Adv Physiol Educ 42: 417-423, 2018). Students' engagement and performance have decreased during COVID-19 because of forced online learning and lack of peer interaction. We hypothesize that creating a nongraded, fun, and relaxing physiology-focused "Trivia Night" will increase student engagement and performance on summative assessments. Using a master's level class progressing through the respiratory physiology module utilizing remote, synchronous lectures to deliver content, we introduced a voluntary Trivia Night review session with teams randomly assigned to increase interaction among peers and review respiratory physiology material.NEW & NOTEWORTHY This article presents the effectiveness of the use of the "pub Trivia Night" to facilitate learning, deconstruct misconceptions, and increase engagement during remote teaching due to the COVID-19 pandemic.

教育工作者面临的一个障碍是,课堂不再局限于一个物理地点,而是学生和教授可以通过互联网会面。在 COVID19 之前,远程或远程学习基本上是学生可以选择是否参与的。学生可以选择学习 "在线课程",无论是同步远程学习还是异步在线课程。事实上,许多研究都侧重于调查许多不同的远程和在线学习方法的效果。不幸的是,COVID 19 强制要求快速过渡到远程学习,而这种被迫的改变也带来了一些学生所描述的 "Zoom 疲劳"[1]。许多学生表示,COVID 大流行所要求的强制性远程教育的急剧增加使他们感到疲惫不堪、不堪重负,并失去了学习兴趣。视频会议已成为这一时期教育的 "灵丹妙药",学生们在屏幕前花费了前所未有的大量时间,而他们通常是在教室里上课。问题:在 COVID 19 期间,由于强制在线学习和缺乏同伴互动,学生的参与度和成绩都有所下降:我们假设,创建一个不分等级的、有趣的、轻松的以生理学为重点的琐事之夜,将提高学生的参与度和在终结性评估中的表现:建议:引入自愿性的 "琐事之夜 "复习课程,以增加同学之间的互动,并复习呼吸生理学材料。
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引用次数: 0
A lesson for us all: the Hodgkin-Keynes long pore model of ion flux. 给我们所有人上了一课:霍奇金-凯恩斯离子通量长孔模型。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-08-29 DOI: 10.1152/advan.00124.2024
Amy J Hopper, Angus M Brown

In this article we analyze the classic Hodgkin and Keynes 1955 paper describing investigations of the independence principle, with the expectation that there is much students and educators can learn from such exercises, most notably how the authors applied their diverse skill set to tackling the numerous obstacles that the study presented. The paper encompasses three of the physiology core concepts, cell membranes, flow down gradients, and scientific reasoning, which were recently assigned to the classes The Biological World, The Physical World, and Ways of Looking at the World, respectively. Thus, analysis of such a paper illuminates the relationships that exist between distinct concepts and encourages a holistic approach to understanding physiology. In-depth analysis of the paper allows us to follow the authors' thought processes from their realization that previous methods lacked the resolution to answer a fundamental question relating to ion movement across membranes to the application of a more sensitive technique and ultimately the development of a novel model describing ion flux. This paper was the culmination of work started in the mid-1930s, strongly supported the ionic theory of nervous conduction proposed by Hodgkin and Huxley, and predicted the presence of ion channels as narrow pores through which ions move sequentially four decades before these features were convincingly demonstrated.NEW & NOTEWORTHY We describe in detail Hodgkin and Keynes' investigation of the independence principle. It is our expectation that students and educators can benefit from following the thought processes applied by the authors as they navigated the complexities of experimental design and data analysis, culminating in development of a model whose elegant simplicity was convincing evidence of narrow membrane-bound pores, ion channels, that were the conduit for transmembrane ion movement.

在这篇文章中,我们分析了霍奇金和凯恩斯 1955 年发表的描述独立原理研究的经典论文,希望学生和教育工作者能从这类练习中学到很多东西,最值得注意的是作者是如何运用他们的各种技能来解决研究中遇到的无数障碍的。这篇论文包含三个生理学核心概念:细胞膜、顺梯度流动和科学推理,这三个概念最近分别被分配到《生物世界》、《物理世界》和《观察世界的方法》课程中。因此,对这样一篇论文的分析可以揭示不同概念之间的关系,并鼓励以整体方法来理解生理学。通过对论文的深入分析,我们可以了解作者的思维过程,从他们意识到以前的方法缺乏分辨率,无法回答与离子跨膜运动有关的基本问题,到应用更灵敏的技术,并最终开发出描述离子通量的新模型。这篇论文是 20 世纪 30 年代中期开始的工作的结晶,有力地支持了霍奇金和赫胥黎提出的神经传导离子理论,并预测了离子通道作为离子依次通过的狭窄孔道的存在,这比这些特征得到令人信服的证实早了 40 年。
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引用次数: 0
The foundation of excitation-contraction coupling in skeletal muscle: communication between the transverse tubules and sarcoplasmic reticulum. 骨骼肌兴奋-收缩耦合的基础:横纹肌小管与肌浆网之间的沟通。
IF 1.7 4区 教育学 Q2 EDUCATION, SCIENTIFIC DISCIPLINES Pub Date : 2024-12-01 Epub Date: 2024-08-08 DOI: 10.1152/advan.00086.2024
Jack A Rall

The expression excitation-contraction (EC) coupling in skeletal muscle was coined in 1952 (Sandow A. Yale J Biol Med 25: 176-201, 1952). The term evolved narrowly to include only the processes at the triad that intervene between depolarization of the transverse tubular (T-tubular) membrane and Ca2+ release from the sarcoplasmic reticulum (SR). From 1970 to 1988, the foundation of EC coupling was elucidated. The channel through which Ca2+ was released during activation was located in the SR by its specific binding to the plant insecticide ryanodine. This channel was called the ryanodine receptor (RyR). The RyR contained four subunits that together constituted the "SR foot" structure that traversed the gap between the SR and the T-tubular membrane. Ca2+ channels, also called dihydropyridine receptors (DHPRs), were located in the T-tubular membrane at the triadic junction and shown to be essential for EC coupling. There was a precise relationship between the two channels. Four DHPRs, organized as tetrads, were superimposed on alternate RyRs. This structure was consistent with the proposal that EC coupling was mediated via a movement of intramembrane charge in the T-tubular system. The speculation was that the DHPR acted as a voltage sensor transferring information to the RyRs of the SR by protein-protein interaction causing the release of Ca2+ from the SR. A great deal of progress was made by 1988 toward understanding EC coupling. However, the ultimate question of how voltage sensing is coupled to the opening of the SR Ca2+ release channel remains unresolved.NEW & NOTEWORTHY The least understood part of the series of events in excitation-contraction coupling in skeletal muscle was how information was transmitted from the transverse tubules to the sarcoplasmic (SR) and how Ca2+ was released from the SR. Through an explosion of technical approaches including physiological, biochemical, structural, pharmacological, and molecular genetics, much was discovered between 1970 and 1988. By the end of 1988, the foundation of EC coupling in skeletal muscle was established.

骨骼肌中的兴奋-收缩(EC)耦合这一说法诞生于 1952 年(1)。该术语狭义地演变为只包括横小管(T-tubular)膜去极化和肌浆网(SR)释放 Ca2+ 之间的三联体过程。从 1970 年到 1988 年,EC 耦合的基础被阐明。激活过程中释放 Ca2+ 的通道通过与植物杀虫剂雷诺丁的特异性结合被定位在 SR 中。这一通道被称为雷诺丁受体(RyR)。RyR 包含四个亚基,共同构成 "SR 足 "结构,穿越 SR 和 T 管膜之间的间隙。Ca2+通道,也称为二氢吡啶受体(DHPRs),位于三联体交界处的T管膜上,对心肌耦合至关重要。这两种通道之间存在着精确的关系。四个 DHPRs 以四分体的形式叠加在交替的 RyRs 上。这种结构与 EC 耦合是通过 T 管系统中的膜内电荷移动介导的这一提议相一致。根据推测,DHPR 起着电压传感器的作用,通过蛋白质与蛋白质之间的相互作用将信息传递给 SR 的 RyR,从而导致从 SR 释放 Ca2+。到 1988 年,在理解 EC 耦合方面取得了很大进展。然而,电压感应如何与 SR Ca2+ 释放通道的开启相耦合这一终极问题仍未解决。
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