Neurobiologist Jean-Pierre Changeux tells us the story of the nicotinic acetylcholine receptor

Forty years ago, we isolated the nicotinic acetylcholine receptor in collaboration with a Taiwanese colleague using an unusual marker – a snake venom toxin. This was the beginning of an extraordinary scientific journey. And 2018 is rather a special year for me as it is the twentieth anniversary of an important article describing how the brain nicotinic receptor is involved in nicotine dependence (see inset below). Against this backdrop, I accepted an offer from the scientific journal Trends in Neuroscience to publish an article addressing a specific chapter in the nicotinic acetylcholine receptor story, namely how the structure of the ion channel linked to the receptor was identified. This was an important step in research on the receptor.

It all started with the very notion of receptors. This notion is the legacy of Claude Bernard's work, which was continued by scientists in England. In the nineteenth century, Claude Bernard demonstrated that curare (used in general anesthesia) worked at the junction between nerve and muscle cells causing paralysis and loss of muscle tone. In 1905, the British physiologist John Newport Langley demonstrated that curare acts on the muscle side of the neuromuscular junction in a structure that he described as a 'receptive substance' or receptor. Langley pioneered research on the effects of curare, demonstrating that it inhibited the effects of nicotine since nicotine triggers muscle contraction and curare inhibits this effect on muscle.

Later, in the 1930s, Otto Loewi and Sir Henry Dale demonstrated acetylcholine's action as a neurotransmitter. Extensive electrophysiological and pharmacological research was subsequently carried out with a view to understanding what happens in nerves and the contacts (or synapses) between nerve endings and their targets when neural signals are transmitted, a process known as chemical synaptic transmission. However, this all took place after the Second World War.

Previous biochemical studies had failed because insufficiently specific molecules had been used for tagging. By introducing a specific marker and using fish electric organ, a type of tissue that is abundant in cholinergic synapses [as demonstrated by David Nachmansohn in 1936 while working in Paris] it was possible to isolate the nicotine receptor studied by Langley. In the 1970s, I met a Taiwanese pharmacologist named Chen-Yuan Lee who was introduced to me by France Depierre, a talented researcher at the Institut Pasteur. This was to prove crucial. France was a student of Daniel Bovet in the great Pasteur tradition of medicinal chemistry [editor's note: she was also married to the vulcanologist Haroun Tazieff]. Although numerous teams were competing against each other at the time, we were the first to isolate the acetylcholine receptor thanks to the exceptional specificity of the toxin produced by the many-banded krait. The receptor was subsequently purified and the first components of its amino acid sequence were established by the Institut Pasteur. These were then confirmed by a host of researchers from around the world, in particular my eminent Japanese colleague, Shosaku Numa, who was the first to publish the entire Torpedo acetylcholine receptor sequence.

That’s right. Physiologists throughout the world were keen to identify this ion channel whose opening was observed when acetylcholine was applied. The assumption was that this channel was located in the part of the receptor that crosses the synaptic membrane, i.e. the transmembrane segments. In the 1980s, Jérôme Giraudat from my lab located the channel in segment MII by identifying one of the components of this channel, serine 262 [editor's note: by photochemical labeling using a channel blocker]. The researchers Shosaku Numa and Henry A. Lester [editor's note: a former post-doctoral fellow with Jean-Pierre Changeux] confirmed and documented this site based on directed mutagenesis analyses while also providing details of new structural elements of the channel.

Yes it was. This was the first time an ion channel's structure had been identified. The nicotinic receptor was also the first neurotransmitter membrane receptor to be discovered in the nervous system. This marks an important step in the history of neuroscience. We also demonstrated that although the ion channel is structurally separate from the site to which acetylcholine binds, this site remotely controls the opening of the channel. This is therefore an example of an allosteric interaction*.

* Allostery is a concept developed by Jacques Monod, Jean-Pierre Changeux and Jeffries Wyman in a series of articles; the main article in this series was published in the Journal of Molecular Biology in 1965: On the nature of allosteric transitions: a plausible model. Monod J, Wyman J, Changeux JP. J Mol Biol. 1965 May;12:88-118.

As is often the case in science, it is definitely true that this work was carried out by teams of researchers from around the world. And I should add that the story of this discovery shows that brain biology, which was for decades the domain of anatomists and physiologists, underwent a sort of revolution with the advent of molecular biology, a discipline in which the Institut Pasteur plays a leading role.