Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine.
Nicotinic receptors also respond to drugs such as the agonist nicotine.
They are found in the central and peripheral nervous system, muscle, and many other tissues.
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 nicotinic receptors transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system; and are the receptors found on skeletal muscle that receives acetylcholine released to signal for muscular contraction.
In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways.
The nicotinic receptors are considered cholinergic receptors, responding to acetylcholine.
Acetylcholine itself binds to both muscarinic and nicotinic acetylcholine receptors.
Nicotinic receptors help transmit signals for the sympathetic and parasympathetic systems, while nicotinic receptor antagonists such as hexamethonium interfere with the transmission of these signals.
Nicotinic receptor antagonists interfere with the baroreflex that normally corrects changes in blood pressure by sympathetic and parasympathetic stimulation of the heart.
Nicotinic receptors are 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 ((α1)2β1γδ), or the adult form composed of α1, β1, δ, and ε subunits in a 2:1:1:1 ratio ((α1)2β1δε).
Opening of the nAChR channel pore requires the binding of a chemical messenger.
Agonists of the nAChR include nicotine, epibatidine, and choline.
Nicotinic antagonists that block the receptor include mecamylamine, dihydro-β-erythroidine, α-bungarotoxin, 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.
Binding of an agonist stabilizes the open and desensitized states.
Opening of the channel allows positively charged ions to move across it; in particular, sodium enters the cell and potassium exits.
The net flow of positively charged ions is inward.
The nAChR is a non-selective cation channel permeable to Na+ and K+, with some subunit combinations that are also permeable to Ca2+.
Many neuronal nAChRs can affect the release of other neurotransmitters.
The channel usually opens rapidly and tends to remain open until the agonist diffuses away, which usually takes about 1 millisecond.
The nAChR is unable to bind ACh when bound to any of the snake venom α-neurotoxins.
These α-neurotoxins antagonistically bind tightly and noncovalently to nAChRs of skeletal muscles and in neurons, thereby blocking the action of ACh at the postsynaptic membrane, inhibiting ion flow and leading to paralysis and death.
The activation of receptors by nicotine modifies the state of neurons by the movement of cations causes a depolarization of the plasma membrane which results in an excitatory postsynaptic potential in neurons leading to the activation of voltage-gated ion channels.
Activation of receptors by nicotine modifies the state of neurons by the entry of calcium acts, either directly or indirectly, on different intracellular cascades, leading to the regulation of activity of some genes or the release of neurotransmitters.
Prolonged or repeated exposure to a stimulus often results in decreased responsiveness of that receptor toward a stimulus, termed desensitization.
After prolonged receptor exposure to the agonist, the agonist itself causes an agonist-induced conformational change in the receptor, resulting in receptor desensitization.
Nicotinic receptors belong to a multigene family (16 members in humans) with highly variable kinetic, electrophysiological and pharmacological properties, responding to nicotine differently, at very different effective concentrations.
This functional diversity allows them to take part in two major types of neurotransmission: Classical synaptic transmission involving the release of high concentrations of neurotransmitter, acting on immediately neighboring receptors; paracrine transmission involves neurotransmitters released by axon terminals, which then diffuse through the extra-cellular medium until they reach their receptors, which may be distant.
Nicotinic receptors can also be found in different synaptic locations; both post-synaptically (involved in classical neurotransmission) and pre-synaptically.
Nicotine addiction arises from nAChR-mediated dopamine release in the mesolimbic pathway.
17 nAChR subunits have been identified, which are divided into muscle-type and neuronal-type subunits. Although an α8 subunit/gene is present in avian species such as the chicken, it is not present in human or mammalian species.
Genetic studies have identified single nucleotide polymorphisms (SNPs) in the chromosomal locus encoding three nAChR genes as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease.
Synthetic / pharmacological agonists
Succinylcholine – depolarizing neuromuscular blocker
Smoking cessation & CNS-acting partial agonists Varenicline Cytisine