I have always been fascinated by the series of studies in electrophysiology that led to our current understanding of how electrical signalling takes place in neurons. And no collection of classical electrophysiology is complete without the 1952 article by AL Hodgkin and AF Huxley on the sodium and potassium currents in the giant axon of the squid.
Saying that Hodgkin and Huxley were brilliant minds would be an understatement. But I was always fascinated by the following phrase in this paper:
‘These results support the view that depolarization leads to a rapid increase in permeability which allows sodium ions to move in either direction through the membrane.’
The reason it fascinates me is that this phrase would not look out-of-place in any modern neurophysiology textbook. But the state of knowledge at the time about how cell membranes were organised was quite different to that of today. Back at that time, cell membranes were thought to be formed by a layer of lipids ‘sandwiched’ between 2 layers of proteins. That meant that for ions to move in and out of the membrane they would have to break through the protein layers and move through the non-aqueous fatty acid layer (something that would be thermodynamically hard for ions to do). Or, something had to ‘open up’ in the membrane to create an aqueous path for the ions to move.
The idea of pores was not foreign to cell biologists at the time, but the demands of Hodgkin and Huxley’s model of ionic movement in neurons could not be easily reconciled with the (then) current model of the cell membrane structure. Hodgkin and Huxley knew ions had to move rapidly and selectively and that the properties of the membrane changed dynamically for this to happen.
In 1972 Singer and Nicolson published a classic model of the cell membrane. In it they propose that rather than ‘sandwiching’ the lipids, proteins are found in the membranes in two forms: as partially embedded proteins, or as intrinsic proteins that traverse the entirety of the cell membrane. It would not take long to see how these intrinsic proteins could form aqueous channels that would allow ions to move from one side to the other of the membrane. That proteins were able to change their shape had already been shown, and so similar mechanisms could be envisioned for the gating of ion channels.
Neurophysiology would never be the same. By 1976 Neher and Sackmann had published their patch clamp method which allowed them to record currents from single channels (and later won them the Nobel Prize), and only two years later Bertil Hille had written and extensive review on ion channels.
It has never been clear to me (or my friends) how much thought Hodgkin and Huxley put into the structure of the cell membrane and how their work fit into the models of the time. But I like to think that they did and chose to trust and follow their data, regardless of the conflicts and lack of sleep that may have raised for cell biologists.
- Hodgkin, A. L., & Huxley, A. F. (1952). Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. The Journal of physiology, 116(4), 449.
- Singer, S. J., & Nicolson, G. L. (1972). The fluid mosaic model of the structure of cell membranes. Science (New York, N.Y.), 175(23), 720-731.
- Neher, E., & Sakmann, B. (1976). Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature, 260(5554), 799-802. doi:10.1038/260799a0
- Hille, B. (1978). Ionic channels in excitable membranes. Current problems and biophysical approaches. Biophysical Journal, 22(2), 283-294. doi:10.1016/S0006-3495(78)85489-7
#SciFoo lightning talk [reloaded]