Nicotinic acetylcholine receptor

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system. Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system. The nicotinic receptors are considered cholinergic receptors, since they respond to acetylcholine. Nicotinic receptors get their name from nicotine which does not stimulate the muscarinic acetylcholine receptors but selectively binds to the nicotinic receptors instead. The muscarinic acetylcholine receptor likewise gets its name from a chemical that selectively attaches to that receptor — muscarine. Acetylcholine itself binds to both muscarinic and nicotinic acetylcholine receptors. As ionotropic receptors, nAChRs are directly linked to ion channels. New evidence suggests that these receptors can also use second messengers (as metabotropic receptors do) in some cases. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors. Since nicotinic receptors help transmit outgoing signals for the sympathetic and parasympathetic systems, nicotinic receptor antagonists such as hexamethonium interfere with the transmission of these signals. Thus, for example, nicotinic receptor antagonists interfere with the baroreflex that normally corrects changes in blood pressure by sympathetic and parasympathetic stimulation of the heart. Nicotinic receptors, with a molecular mass of 290 kDa, are made up of five subunits, arranged symmetrically around a central pore. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. They possess similarities with GABAA receptors, glycine receptors, and the type 3 serotonin receptors (which are all ionotropic receptors), or the signature Cys-loop proteins. In vertebrates, nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: muscle-type nicotinic receptors and neuronal-type nicotinic receptors. In the muscle-type receptors, found at the neuromuscular junction, receptors are either the embryonic form, composed of α1, β1, γ, and δ subunits in a 2:1:1:1 ratio, or the adult form composed of α1, β1, δ, and ε subunits in a 2:1:1:1 ratio. The neuronal subtypes are various homomeric (all one type of subunit) or heteromeric (at least one α and one β) combinations of twelve different nicotinic receptor subunits: α2−α10 and β2−β4. Examples of the neuronal subtypes include: (α4)3(β2)2, (α4)2(β2)3, (α3)2(β4)3, α4α6β3(β2)2, (α7)5, and many others. In both muscle-type and neuronal-type receptors, the subunits are very similar to one another, especially in the hydrophobic regions. A number of electron microscopy and x-ray crystallography studies have provided very high resolution structural information for muscle and neuronal nAChRs and their binding domains. As with all ligand-gated ion channels, opening of the nAChR channel pore requires the binding of a chemical messenger. Several different terms are used to refer to the molecules that bind receptors, such as ligand, agonist, or transmitter. As well as the endogenous agonist acetylcholine, agonists of the nAChR include nicotine, epibatidine, and choline. Nicotinic antagonists that block the receptor include mecamylamine, dihydro-β-erythroidine, and hexamethonium. In muscle-type nAChRs, the acetylcholine binding sites are located at the α and either ε or δ subunits interface. In neuronal nAChRs, the binding site is located at the interface of an α and a β subunit or between two α subunits in the case of α7 receptors. The binding site is located in the extracellular domain near the N terminus. When an agonist binds to the site, all present subunits undergo a conformational change and the channel is opened and a pore with a diameter of about 0.65 nm opens.