Hodgkin and Huxley and the basis for electrical signalling: a remarkable legacy still going strong
Hodgkin and Huxley and the basis for electrical signalling: a remarkable legacy still going strong
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霍奇金和赫胥黎以及电信号的基础：一项非凡的遗产仍然很强大
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
S. Waxman
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作者：
J. Vandenberg;S. Waxman
电信号在神经和其他可兴奋组织中的起始和传播已经吸引了生理学家超过世纪。在世纪上半叶的大部分时间里，对动作电位过程中发生的去极化的普遍解释是伯恩斯坦在1902年提出的“膜破裂”。他提出，在静息状态下，细胞膜对K+离子具有选择性渗透性，K+离子倾向于沿着电化学梯度扩散出细胞，并保持负的静息膜电位。根据该模型，然后通过所有离子的渗透性的瞬时增加触发动作电位，因此细胞膜电位将接近零。在20世纪30年代末和40年代初，美国的Curtis &科尔（1942）和英国的Hodgkin & Huxley（1939）提供了明确的证据，证明在动作电位期间，膜电位大大超过0 mV。这与“膜破裂”假说不一致，而是表明在去极化过程中，膜仍然选择性地渗透某些离子，但显然不是K+离子。
1946年至1952年间，霍奇金和赫胥黎，最初与伯纳德·卡茨合作，开始使用新开发的电压钳技术，剖析鱿鱼巨轴突动作电位传播过程中发生的选择性渗透性变化的基础。1952年，他在《生理学杂志》上发表了五篇开创性的论文。1952年4月背靠背发表的前四篇实验论文描述了（i）鱿鱼巨轴突膜中电流-电压关系的测量（Hodgkin等人，1952年），（ii）钠离子和钾离子携带电流的基本特征（Hodgkin & Huxley，1952 a），（iii）改变去极化和复极化步骤的时间和持续时间对膜电流的不同成分的影响（Hodgkin & Huxley，1952 b）和（iv）在钠渗透性经历了与去极化相关的初始升高后逐渐降低钠渗透性的“失活”过程（Hodgkin & Huxley，1952 c）。在1952年8月发表的五篇论文的最后一篇中，霍奇金和赫胥黎通过提供“膜电流的定量描述及其在神经传导和兴奋中的应用”（Hodgkin & Huxley，1952 d）综合了他们的结果。这篇最后的论文仍然是生物科学中计算机建模最优雅的例子之一。它被引用的频率（总共超过9000次，仅在过去12个月内就超过300次）不仅证明了它代表了膜生理学和电信号研究的真正范式转变，而且证明了它的逻辑性和清晰度。这确实是一个必须阅读的文件，甚至超过半个世纪。
尽管这些开创性的论文发表已经过去了60年，但它们仍然激励着生理学及其现代后代“系统生物学”的几乎所有分支的研究。它们还刺激了最基础层面的研究，从离子通道的原子分辨率结构分析，到可能很快为兴奋性障碍提供新疗法的创新临床研究。为了庆祝《1952年赫胥黎论文集》出版60周年，我们在这期特刊中收录了一系列评论，这些评论反映了赫胥黎论文集的历史意义和现代遗产。我们从历史概述（Schwiening，2012）开始，然后是钠通道（卡特拉尔，2012）和钾通道（Jan & Jan，2012）的概述，以及霍奇金和赫胥黎的开创性工作如何继续激发这些通道的工作。随后进行了一项审查，检查了Hodgkin-Huxley遗传病和钠通道病的临床意义（Waxman，2012）。最后，我们对心脏的计算机建模进行了概述（Noble et al. 2012），这是系统生物学研究的一个非常富有成效的领域，其起源可以直接追溯到Hodgkin和Huxley的工作。除了这个特别关注的问题，生理学杂志还发布了一个特殊的在线问题，其中原始1952年的论文可沿着数百篇论文的选择，这些论文受到霍奇金和赫胥黎的工作的启发，随后发表在生理学杂志上（见http：//jp.physoc.org/site/misc/virtualissues_archive.xhtml）
展望未来，我们预计Hodgkin-Huxley的贡献将继续推动生物医学研究，包括肌肉生理学和药理学，自主生理学，神经科学，疾病病理生理学甚至临床医学等领域。
The initiation and propagation of electrical signals in nerves and other excitable tissues have fascinated physiologists for well over a century. For much of the first half of the twentieth century the prevailing explanation for the depolarization occurring during an action potential was that of ‘membrane-breakdown’ suggested by Bernstein in 1902. He proposed that at rest the cell membrane was selectively permeable to K+ ions, which would tend to diffuse out of the cells down their electrochemical gradient and maintain a negative resting membrane potential. According to this model an action potential was then triggered by a transient increase in permeability for all ions and hence the cell membrane potential would approach zero. In the late 1930s and early 1940s Curtis & Cole (1942) in the United States and Hodgkin & Huxley (1939) in the United Kingdom, provided definitive evidence that during an action potential the membrane potential greatly exceeded 0 mV. This was inconsistent with the ‘membrane-breakdown’ hypothesis but rather suggested that during depolarization the membrane was still selectively perme-able to some ions, but clearly not K+ ions.
Between 1946 and 1952, Hodgkin and Huxley, initially in collaboration with Bernard Katz, set about using the newly developed voltage-clamp technique, to dissect the basis of the changes in selective permeability that occur during propagation of action potentials in the squid giant axon. This culminated in the publication of five seminal papers in The Journal of Physiology in 1952. The first four experimental papers, published back-to-back in April 1952, described (i) the measurement of current–voltage relationships in the membrane of the squid giant axon (Hodgkin et al. 1952), (ii) basic characteristics of the currents carried by sodium and potassium ions (Hodgkin & Huxley, 1952a), (iii) the effect of varying the time and duration of depolarization and repolarization steps on the different components of membrane current (Hodgkin & Huxley, 1952b), and (iv) the ‘inactivation’ process which gradually reduces sodium permeability after it has undergone the initial rise associated with depolarization (Hodgkin & Huxley, 1952c). In the final of the five papers, published in August 1952, Hodgkin and Huxley synthesized their results by providing a ‘quantitative description of membrane current and its application to conduction and excitation in nerve’ (Hodgkin & Huxley, 1952d). This final paper is still one of the most elegant examples of computer modelling in biological sciences. The frequency with which it is cited (over 9000 times in total and over 300 times in the last 12 months alone) is testament not just to the fact that it represents a genuine paradigm shift in the study of membrane physiology and electrical signalling but also to its incisive logic and clarity of presentation. It truly is a must read paper even more than half a century on.
Although 60 years have passed since these pioneering papers were published, they still stimulate research in almost all branches of physiology and its modern descendent, ‘systems biology’. They have also stimulated research at the most fundamental level, ranging from atomic resolution structural analysis of ion channels, through to innovative clinical research that may soon deliver new therapies for disorders of excitability. To celebrate the 60th anniversary of the ‘1952 Hodgkin Huxley papers’, we have included in this special issue a series of reviews that reflect on both the historical significance and the modern legacy of their work. We start with a historical overview (Schwiening, 2012), followed by overviews of sodium channels (Catterall, 2012) and potassium channels (Jan & Jan, 2012) and how the pioneering work of Hodgkin and Huxley continues to inspire work on these channels. This is followed by a review that examines the clinical significance of the Hodgkin–Huxley legacy and sodium channelopathies (Waxman, 2012). Lastly we have an overview on computer modelling of the heart (Noble et al. 2012), a remarkably productive area of systems biology research, which can trace its origins directly to the work of Hodgkin and Huxley. In addition to this special focused issue, The Journal of Physiology has released a special online-only issue in which the original 1952 papers are available along with a selection of the many hundreds of papers inspired by the work of Hodgkin and Huxley and subsequently published in The Journal of Physiology (see http://jp.physoc.org/site/misc/virtualissues_archive.xhtml)
Looking forward, we expect that the Hodgkin–Huxley contribution will continue to propel biomedical research, in areas as diverse as muscle physiology and pharmacology, autonomic physiology, neuroscience, disease pathophysiology and even clinical medicine.