Acetylcholine

Acetylcholine, often abbreviated to Ach, is a neurotransmitter found in the autonomic nervous system of both vertebrates and invertebrates. It was first identified in 1914 by Henry Dale and confirmed as a neurotransmitter by Otto Loewi. In 1936 they both received a Nobel prize for their work in Medicine.

Chemical Structure

Ach is an ester of acetic acid and choline and has a systemic name of 2-(acetyloxy)-N,N,N-trimethylethanaminium.

Acetylcholine is released and found in the preganglionic and postganglionic neurons of the parasympathetic nervous system. It is also present in the preganglionic neurons of the sympathetic nervous system. In these nervous systems Ach binds to two different types of receptors- the nicotinic Ach receptor annd the muscarinic Ach receptor. The nicotinic Ach receptor is a ionotropic receptor and can be atagonised by the poison curare. The muscarinic Ach receptor is a metabotropic receptor and is antagonised by the chemical compound atropine. There are actually many different subtypes of Ach GPCRs, which can be categorised in terms of their associated G protein. For instance, M₂ and M₄ are coupled with G_i/G_o whilst M₁, M₃ and M₅ are coupled with G_q/₁₁.

Signalling Pathways

Within Vertebrates, Acetylcholine is most commonly found in the brain and is indeed often considered the main excitatory neurotransmitter. It is exceptionally diverse in that it is able to function via two different pathways. Firstly via Ligand-Gated ion channels, also used by neurotransmitters such as Glutamate and Glycine, which involve the use of Ionotropic Receptors. During this process, Acetylcholine is released from presynaptic neurones within vesicles, which diffuse across the synapse towards the postsynaptic neurone. On the surface of the postsynaptic neurone are complementary ionotropic receptor proteins, which receive the Acetylcholine. The binding of Acetylcholine to its ionotropic receptor causes the opening of Ligand-gated ion channels in the postsynaptic neurone and hence the release of Sodium ions (during an EPSP) in turn causing the action potential to be generated in the postsynaptic neurone. For the conformation change to occur, two molecules of acetylcholine must bind to ensure the gated ion channel remains open until hydrolysation occurs. However, if it is not hydrolysed, inactivation will occur causing the channel to close even with acetylcholine bound to it. This usually occurs if the molecules are not hydrolysed within 20 milliseconds.

Secondly, acetylcholine can be received by metabotropic receptors which are frequently found in the heart. Here, the binding of acetylcholine to its metabotropic receptor causes a series of changes within a signalling pathway, resulting in the opening of potassium channels in the muscle cell membrane. This has a parasympathetic effect on the heart rate.

Acetylcholinesterase is the hydrolase enzyme involved in the breakdown of acetylcholine. This enzyme is present in the synaptic cleft and breaks down acetylcholine into choline and acetate. These inactive metabolites can then re-cycle acetylcholine after diffusing back into the pre-synaptic membrane. Sarin is an example of a cholinesterase inhibitor which prevents hydrolysis of acetlycholine.