From Bernstein's rheotome to Neher-Sakmann's patch electrode. The action potential.

The aim of this review was to provide an overview of the most important stages in the development of cellular electrophysiology. The period covered starts with Bernstein's formulation of the membrane hypothesis and the measurement of the nerve and muscle action potential. Technical innovations make discoveries possible. This was the case with the use of the squid giant axon, allowing the insertion of "large" intracellular electrodes and derivation of transmembrane potentials. Application of the newly developed voltage clamp method for measuring ionic currents, resulted in the formulation of the ionic theory. At the same time transmembrane measurements were made possible in smaller cells by the introduction of the microelectrode. An improvement of this electrode was the next major (r)evolution. The patch electrode made it possible to descend to the molecular level and record single ionic channel activity. The patch technique has been proven to be exceptionally versatile. In its whole-cell configuration it was the solution to measure voltage clamp currents in small cells. See also: https://doi.org/10.14814/phy2.13860 & https://doi.org/10.14814/phy2.13862.

The glass micropipette electrode: A history of its inventors and users to 1950.

Soon after the glass micropipette was invented as a micro-tool for manipulation of single bacteria and the microinjection and microsurgery of living cells, it was seen to hold promise as a microelectrode to stimulate individual cells electrically and to study electrical potentials in them. Initial successes and accurate mechanistic explanations of the results were achieved in giant plant cells in the 1920s. Long known surface electrical activity in nerves and muscles was only resolved at a similar cellular level in the 1930s and 1940s after the discovery of giant nerve fibers and the development of finer tipped microelectrodes for normal-sized cells.

History of electrophysiology and the patch clamp.

We provide a historic outlook on the development of the concept of bioelectricity, with emphasis on the neuromuscular junction as a model that revolutionized our thinking of the nerve, nervous, and muscle tissue excitability. We abridge some crucial experiments in defining the electrical excitability of biological cells. We also provide an insight into developments of tools and methods, which gradually yielded a contemporary "palette" of electrophysiology approaches, including the patch clamp. Pioneering steps in this journey, ranging from Galvani's experiments using the Leyden jar to those of Neher and Sakmann using a gigaseal patch-clamp approach, are pictorially illustrated. This chapter is meant to be a perspective to the following sections in this volume dedicated to patch-clamp methods and protocols.

How the early voltage clamp studies of José del Castillo inform "modern" neuroscience.

The description of ionic currents that flow across the membrane of the squid giant axon during an action potential sparked an interest in determining whether there were similar currents in vertebrates. The preparation of choice was the node of Ranvier in single myelinated fibers in frog. José del Castillo spent 3 years on the United States mainland from 1956 to 1959. During that time, he collaborated with Jerome Y. Lettvin and John W. Moore. I discuss how these individuals met one another and some of their scientific discoveries using the voltage clamp to study squid giant axons and frog nodes. Much of this work was conducted at the Marine Biological Laboratory in Woods Hole, MA, and I attempt to convey a sense of the unique scientific "melting pot" that existed at the Marine Biological Laboratory and the broader effect that del Castillo had on "modern" neuroscience.

The FGIN period: electrophysiological studies.

This historical review of the electrophysiology laboratory complemented the activity of the various research teams at the Fidia Georgetown Institute for the Neurosciences and it was the fulfillment of Dr. Erminio Costa's dream to be able to study the inhibitory and excitatory synapse in the central nervous system. These studies were facilitated by the development of the patch clamp technique that allows the functional testing of several of the biochemical and pharmacological hypotheses. The studies described here were the results of the hard work of all the collaborators involved in the projects that will never forget the passionate and stimulating discussion with Dr Costa during and after the development of these projects.

Real-time closed-loop electrophysiology: towards new frontiers in in vitro investigations in the neurosciences.

Reflected at any level of organization of the central nervous system, most of the processes ranging from ion channels to neuronal networks occur in a closed loop, where the input to the system depends on its output. In contrast, most in vitro preparations and experimental protocols operate autonomously, and do not depend on the output of the studied system. Thanks to the progress in digital signal processing and real-time computing, it is now possible to artificially close the loop and investigate biophysical processes and mechanisms under increased realism. In this contribution, we review some of the most relevant examples of a new trend in in vitro electrophysiology, ranging from the use of dynamic-clamp to multi-electrode distributed feedback stimulation. We are convinced these represents the beginning of new frontiers for the in vitro investigation of the brain, promising to open the still existing borders between theoretical and experimental approaches while taking advantage of cutting edge technologies.

From Galvani to patch clamp: the development of electrophysiology.

The development of electrophysiology is traced from the early beginnings represented by the work of the Dutch microscopist, Jan Swammerdam, in the 17th century through the first notion of an aqueous transmembrane pore as a substrate of excitability made by Luigi Galvani in late 18th century to the invention late in the 20th century of the patch-clamp technique by Erwin Neher and Bert Sakmann.

Ca2+ signalling and Ca2+-activated ion channels in exocrine acinar cells.

The development of the calcium signalling field, from its early beginnings some 40 years ago to the present, is described. Calcium signalling in exocrine gland acinar cells and the effects of neurotransmitter- or hormone-elicited rises in the cytosolic calcium ion concentration on ion channel gating are reviewed. The highly polarized arrangement of the organelle systems in living acinar cells is described as well as its importance for the physiologically relevant local and polarized calcium signalling events.

Pflügers Archiv and the advent of modern electrophysiology. From the first action potential to patch clamp.

This short review recollects the many essential milestones in electrophysiology that were published in Pflügers Archiv. These involve the first measurement of an action potential by J. Bernstein, the requirement of Na+ for the generation of excitation, the prediction of a lipoid membrane surrounding cells by E. Overton, the physical explanation of the resting membrane potential by J. Bernstein, the first detailed description of the conductance properties of excitable tissues by L. Hermann, and more recently the publication of the patch-clamp method by E. Neher and B. Sakmann.

Fifty years of the Hodgkin-Huxley era.

Modern neuroscientists are accustomed to the detailed information on the structure and function of membrane ion channels that can be obtained by the combination of molecular biology, crystallography and patch-clamp recordings. It can be difficult for us to appreciate how hard it was for humankind to realize that physical events underlie nervous function and, moreover, to appreciate how long it took to devise a realistic model for the generation and propagation of the nerve impulse.

From overshoot to voltage clamp.

In 1939, A.L. Hodgkin and I found that the nerve action potential shows an "overshoot"--that is, the interior of the fibre becomes electrically positive during an action potential. In 1948, we did our first experiments with a voltage clamp to investigate the current-voltage relations of the nerve membrane. Between those dates, we spent much time speculating about the mechanism by which ions cross the membrane and how the action potential is generated. This article summarizes these speculations, none of which has been previously published.