A brief history of the discovery of ion channels

Introduction to transmembrane proteins : the ion channel class


Membranes are the building blocks of life.


Three billion years ago, lipid layers allowed first primitive forms of life to retain and protect their vital elements by creating a barrier with their threatening environment.


But no one survives in total autarky.


And integrity without interaction is a dead-end.


In fact, how can genetic material be transferred to the next generation without constantly exchanging with the environment?


Since the bacteria wanted to continue to protect themselves from outside danger, evolution provided the solution. And Life began recruiting bouncers.


Embedded in the lipid bilayer membrane of animals, plant cells and their respective organelles, these “bouncers” - called membrane proteins - control the entities in the extra-cellular environment and select those that can “party” inside the cell.


Membrane proteins are the most represented structures of the entire biologic reign. These remarkable structures are the selective gateways to living organisms, and represent a third of all proteins in human cells. Amongst them, we can find G protein-coupled receptors (GPCRs), transporters and ion channels.


Today, let’s focus on the last ones.


Animal electricity: a first visible evidence of ion channels


Luigi Galvani was a well-known medicine lecturer at the University of Bologna, in Italy. Assisted by his wife, Luigi used to practise a lot the subtle art of surgery on animals (1).


One day, vivisecting layer by layer a frog's leg, a spark from Galvani’ metal scalpel suddenly appeared when it came in contact with the animal nerves. Astonishingly, the dead member of the batrachian regained life and its legs jerked into motion. Galvani called this amazing movement “animal electricity” and the phenomenon rapidly being known as “Galvanism”.


The discovery of neurotransmitters: Galvanism becomes electrophysiology


But until 1920, no scientist had any clue how a nerve simulation was transmitted to the effector organ. It was commonly thought to occur by direct transmission of the stimulation wave from the nerve fiber to the effector organ.


In 1921, Henry Dale - thanks to the isolation of acetylcholine (2) - and his colleague Otto Loewi (3, 4, 5, 6, 7, 8) demonstrated the electrochemical nature of nervous transmission and paved the way to ion channel discovery.


Electrophysiology in times of war: the birth of neurobiology


After completing a medical degree in 1915, Edgar Douglas Adrian was confronted with practical electrophysiology at the time of World War I, treating soldiers with nerve damage and post-traumatic stress disorder.


In 1928, he noted a curious finding during one of its experiment using its capillary electrometer on toad: “The explanation suddenly dawned on me... a muscle hanging under its own weight ought, if you come to think of it, to be sending sensory impulses up the nerves coming from the muscle spindles...That particular day’s work, I think, had all the elements that one could wish for. The new apparatus seemed to be misbehaving very badly indeed, and I suddenly found it was behaving so well that it was opening up an entire new range of data... it didn’t involve any particular hard work, or any particular intelligence on my part. It was just one of those things which sometimes happens in a laboratory” (9).


The squid giant axon experiment


Joseph Erlanger, brilliant cardiologist, was fascinated in the way that excitation transferred from the atrium to the ventricle. He was the first to record nerve impulses with a cathode ray oscilloscope and valve amplifier he set-up by himself. With his colleague Blair, Erlanger concluded that an impulse which arrived at a blocked region could increase excitability in the nerve beyond the block.


In 1937, pursuing the work of Erlanger, Alan Lloyd Hodgkin was wondering if the local circuits set up by an active region of a nerve fibre are able to excite an adjacent part. Working on giant nerve fibres in the squid - discovered by Young (10) - Alan and his partner Andrew Huxley manage to introduce voltage clamp electrodes inside the lumen of the axon to record the potential difference across the membrane (11).


Isolation of a single ion channel


As early as 1954, Bernard Katz submitted the idea of single ion channels. Using intracellular microelectrodes, Katz and his co-workers discovered miniature endplate potentials (MEPPs) and explained their origin by the quantal hypothesis (small packages) of transmitter release: "Transmission at a nerve–muscle junction takes place in all-or-none 'quanta' whose sizes are indicated by the spontaneously occurring miniature discharges"(12). But at that time, measuring currents at a single ion channel level was still not technically possible.


In 1978, Neher and Sakmann made the practical demonstration of Katz’s hypothesis thanks to the invention of the patch clamp, a technique ables to measure tiny currents in biological membranes, allowing the observation of the currents through a single ion channel (13).


Twenty years later, using X-ray crystallography on Actinobacteria, Roderick MacKinnon succeeded in demonstrating what three-dimensional molecular structure of an ion channel looks like (14).


But 1998 is just the beginning of the fantastic history of ion channels…





(1) GALVANI Luigi. De viribus electricitatis in motu musculari, Bononiae - Institutus Scientiarium – 1791.


(2) H.H. Dale, J. Pharmacol., 6 (1914) 147.


(3) O. Loewi, Pflügers Arch. Ges. Physiol., 189 (1921) 239.


(4) O. Loewi, Pflügers Arch. Ges. Physiol., 193 (1921) 201.


(5) O. Loewi, Pflügers Arch. Ges. Physiol., 203 (1924) 408.


(6) O. Loewi and E. Navratil, Pflügers Arch. Ges. Physiol., 206 (1924) 123.


(7) O. Loewi and E. Navratil, Pflügers Arch. Ges. Physiol., 214 (1926) 678.


(8) O. Loewi and E. Navratil, Pflügers Arch. Ges. Physiol., 214 (1926) 689.


(9) Adrian ED: The basis of sensation; the action of the sense organs, by E.D. Adrian. London, Christophers, 1928.


(10) The Functioning of the Giant Nerve Fibres of the Squid, J. Z. YOUNG, Journal of Experimental Biology 1938 15: 170-185.


(11) EVIDENCE FOR ELECTRICAL TRANSMISSION IN NERVE. BY A. L. HODGKIN From the Department of Physiology, Cambridge (Received 18 March 1937)


(12) DEL CASTILLO J, KATZ B. Quantal components of the end-plate potential. J Physiol. 1954;124(3):560-573. doi:10.1113/jphysiol.1954.sp005129


(13) Neher, E., Sakmann, B. & Steinbach, J.H. The extracellular patch clamp: A method for resolving currents through individual open channels in biological membranes. Pflugers Arch. 375, 219–228 (1978). https://doi.org/10.1007/BF00584247.


(14) MacKinnon R, Cohen SL, Kuo A, Lee A, Chait BT (April 1998). "Structural conservation in prokaryotic and eukaryotic potassium channels". Science. 280 (5360): 106–9.