Nicotinic acetylcholine receptors, or nAChRs, are Cholinergic receptors that form ligand-gated ion channels in cells' plasma membranes. Like the other type of acetylcholine receptors, muscarinic acetylcholine receptors (mAChRs), their opening is triggered by the neurotransmitter acetylcholine (ACh), but they are also opened by nicotine. Also in contrast to muscarinic ACh receptors, nicotinic receptors do not operate with a second messenger, but open themselves forming an ion channel. Their action is inhibited by curare.
Nicotinic acetylcholine receptors are present in many tissues in the body. The neuronal receptors are found in the central nervous system and the peripheral nervous system. The neuromuscular receptors are found in the neuromuscular junctions of somatic muscles; stimulation of these receptors causes muscular contraction.
StructureNicotinic receptors, with a molecular mass of 290 kDa , are made up of five receptor subunits, arranged symmetrically around the central pore. They share similarities with GABAA receptors, glycine receptors, and the type 3 serotonin receptors, which are all therefore classed in the ionotropic family, or the signature Cys-loop proteins.
Twelve types of nicotinic receptor subunits, α2 through 10 and β2 through 4 (Itier and Bertrand, 2001), combine to form pentamers. The subunits are somewhat similar to one another, especially in the hydrophobic regions. The neuronal forms are much more heterogeneous, with a wide range of possible subunit combinations.
The sites for binding ACh are on the outside of the α subunits near their N termini. and a pore with a diameter of about 0.65 nm opens. Interestingly, because some neuronal nAChRs are permeable to Ca2+, they can affect the release of other neurotransmitters. Prolonged or repeat exposure to a stimulus often results in decreased responsiveness of that receptor for a stimulus. nAChR function can be modulated by phosphorylation by the activation of second messenger-dependent protein kinases. Phosphorylation of the nAChR by PKA have been shown to phosphorylate nAChR resulting in its desensitization. It has been reported that after prolonged receptor exposure to the agonist, the agonist itself causes an agonist-induced conformational change in the receptor, resulting in receptor desensitization. This receptor desensitization has been previously modeled in the context of a two-state mathematical model (see this link http://www.bio-balance.com/Graphics.htm)
RolesThe subunits of the nicotinic receptors belong to a multigene family (17 members in human) and the assembly of combinations of subunits results in a large number of different receptors (For more information see the Ligand-Gated Ion Channel database). These receptors, with highly variable kinetic, electrophysiological and pharmacological properties, respond differently to nicotine, at very different effective concentrations. This functional diversity allows them to take part in two major types of neurotransmission. Classical synaptic transmission (wiring transmission) involves the release of high concentrations of neurotransmitter, acting on immediately neighbouring receptors. In contrast, paracrine transmission (volume transmission) involves neurotransmitters released by synaptic buttons or varicosities, 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, for example the muscle nicotinic receptor always functions post-synaptically. The neuronal forms of the receptor can be found both post-synaptically (involved in classical neurotransmission) and pre-synaptically (where they can influence the release of other neurotranmsitters).
SubunitsTo date 17 nAChR subunits have been identified, these are divided into muscle-type and neuronal-type subunits. Of these 17 subunits, α2-α7 and β2-β4 have been cloned in humans, the remaining genes identified in chick and rat genomes. The nAChR subunits have been divided into 4 subfamilies (I-IV) based on similarities in protein sequence . In addition, subfamily III has been further divided into 3 tribes.
- Alpha genes: (muscle), (neuronal), , , , , , , ,
- Beta genes: (muscle), (neuronal), , ,
- Other genes: (delta), (epsilon), (gamma)
Notable variationsNicotinic receptors are pentamers of these subunits, i.e. each receptor contains five subunits. Thus, there is an immense potential of variation of the aforementioned subunits. However, some of them are more notable than others, specifically (α1)2β1δε (muscle type), (α3)2(β4)3 (ganglion type), (α4)2(β2)3 (CNS type) and (α7)5 (another CNS type). A comparison follows:
nicotinic in German: Nikotinischer Acetylcholinrezeptor
nicotinic in Spanish: Receptor nicotínico
nicotinic in French: Récepteur nicotinique
nicotinic in Italian: Recettore nicotinico
nicotinic in Polish: Receptory nikotynowe
nicotinic in Portuguese: Receptor nicotínico
nicotinic in Ukrainian: Нікотиновий ацетилхоліновий рецептор