Nicotinic Acetylcholine Receptor
Nicotinic Acetylcholine ReceptorThe nicotinic acetylcholine receptor is a key protein in neuronal communication. This protein effectively converts neurotransmitter binding into a membrane depolarization event. The protein combines neurotransmitter binding sites, specifically acetylcholine, with a cationic ion channel, specifically sodium (Na).
StructureThe receptor is a transmembrane pentameric glycoprotein. It has a weight of approximately 300,000 Daltons. It cylindrical in appearance by electron microscopy approximately 16nm in length and 8nm in diameter. The main ion channel is composed of a water pore that runs through the entire length of the protein. If viewed from the synaptic cleft, the protein will look like a pseudo-symmetrical rosette shown in the picture below composed of 10 different alpha and 4 different beta subunits.
ACh Binding SitesThis protein carries anywhere from 2 to 5 acetylcholine binding sites which are located at the interface between two subunits. Each subunit contributes 3 loops to the binding site. There is also a "principle" side and a "complimentary" side of the subunits. The principle side binding nicotine with a high degree of specificity and the complimentary side binding a wide variety of acetylcholine like molecules. See also Binding site of AChR and Acetylcholine Receptor and its Reaction to Cobra Venom. Ion ChannelThe ion channel of the protein is a 20 membered alpha helix bundle. This channel also contributes to the receptor function in three critical aspects: it contains a gating mechanism, it contains a water pore to stabilize ions, and it has a selectivity filter for ion charge. As with most transmembrane alpha helix bundles, it is hydrophobic around the edges to effectively be supported within the membrane, and it is hydrophilic on the inner portion to transport charged ions. PhysiologyThe receptor is a cylindrically-shaped protein. It is embedded in the cell wall of post synaptic nerves at the skeletal neuromuscular junction. The receptor acts as a chemically controlled sodium (Na) channel also known as a ligand gated channel. When in the presence of acetylcholine, the receptor undergoes a conformational change opening up the channel to an influx of sodium (Na) within the cell. When this happens the cell undergoes a depolarization event that triggers an action potential to propagate along the rest of the cell stimulating, for example, a muscle response. The opening of these channels only lasts for a millisecond due to cholinesterase being present and breaking down acetylcholine attached to the receptor causing the receptor to close again. Introduction of Acetylcholinesterase inhibitors can cause a depolarization block. It works by creating a prolonged refractory period in the depolarization event promoted by the opening of the receptor channel. Locations•skeletal neuromuscular junctions •sympathetic and parasympathetic nervous system •autonomic ganglia •central nervous system Clinical FindingsFindings due to nicotinic stimulation from Acetylcholinesterase inhibitors
Below is a mnemonic for remembering nicotinic signs of cholinesterase inhibitor toxicity Monday Mydriasis (pupil dilation) Tuesday Tachycardia Wednesday Weakness Thursday Hypertension Friday Fasciculations See also: 3D Structures of nicotinic acetylcholine receptor |
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ReferencesReferences
1. Cholinesterase Inhibitors: Including Insecticides and Chemical Warfare Nerve Agents, Agency for Toxiz Substances and Disease Regulation accessed 5/2/14
2. Pierre-Jean Corringer and Jean-Pierre Changeux (2008) Nicotinic acetylcholine receptors. Scholarpedia, 3(1):3468.
3. Adcock C, Smith GR, Sansom MS. The nicotinic acetylcholine receptor: from molecular model to single-channel conductance. Eur Biophys J. 2000;29:29–37.