Bringing Structure to Biology
Signalling in motion
The image in PDBe’s 2018 calendar for November shows nerves and muscle tissue, and the molecule which we use to send signals between them.
When a signal in the body is propagated along a nerve cell, it travels electrically, by waves of ions flowing across the nerve cell membranes. Between cells however, an alternative mechanism is needed, and this is the realm of the neurotransmitter. To pass a signal from one nerve cell to the next, or from a nerve to a muscle cell, a chemical neurotransmitter is secreted, flooding the space between the two cells. This space is either a synapse, between two nerve cells, or a neuromuscular junction, between nerves and muscle.
The first neurotransmitter to be identified was acetylcholine, earning Dale and Loewi the 1936 Nobel Prize in Physiology or Medicine. By the standards of the PDB, it’s a tiny molecule with only 26 atoms. But without it, we could not survive.
Receiving the message
Once released from a nerve cell, acetylcholine diffuses across the synapse and binds to receptors on the membrane of the target cell, triggering a response. There are several types of receptors for acetylcholine, which give varied responses. Some are in the G-protein coupled receptor family, such as the muscarinic acetylcholine receptors, so called as they also react to the compound muscarine, found in mushrooms.
Other receptors, such as the nicotinic acetylcholine receptors, are ion channels themselves, binding acetylcholine directly and triggering a flow of ions across the membrane. These receptors, which also respond to the drug nicotine, are the main receptors at the neuromuscular junction.
Shooting the messenger
Once a signal has been passed across a neuromuscular junction or synapse, the signalling molecule needs to be removed. That’s the job of acetylcholinesterase (AChE), which splits acetylcholine into acetate and choline, preventing accumulation of the molecule and therefore avoiding repeated and uncontrolled muscle or nerve stimulation.
AChE one of the fastest enzymes known, catalysing the breakdown of up to 10,000 acetylcholine molecules per second. It’s speed is all the more remarkable given the position of the active site - the place where acetylcholine is broken down. It’s not on the surface of the protein but at the bottom of a 20Å deep channel (see figure). How the acetylcholine is so quick to get to the active site, and the breakdown products so quick to leave it, remains unclear.
Acetylcholine (shown in ball-and-stick) in the active site of acetylcholinesterase. PDB entry 2ace
AChE is such a critical enzyme that it is a target for chemical weapons, pest-control agents, drugs, and even snake venoms. The nerve agent sarin, for example, is a potent inhibitor of AChE. It reacts irreversibly with AChE, inactivating the enzyme permanently. PDB entry 2whp shows AChE inhibited by sarin.
Many drugs target AChE, these include insecticides and dementia medication. In diseases such as Alzheimer’s, certain types of brain cell produce too little acetylcholine. Inhibiting AChE in this case allows what little is produced to deliver its message more times before it is finally broken down. Some of these drugs are derived from natural products, such as galanthamine, which is produced by snowdrops to prevent them from being eaten.
About the artwork
The image is by Martha Vigliotti from Impington Village College. It's a Batik on silk showing a nerve cell and muscle fibre, and overliad with acetylcholine.