Everything about Nicotinic totally explained
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're also opened by
nicotine. Also in contrast to muscarinic ACh receptors, nicotinic receptors don't 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.
Structure
Nicotinic 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 Ca
2+, 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
(External Link
))
Roles
The 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).
Subunits
To 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.
| Neuronal-type |
Muscle-type |
| I |
II |
III |
IV |
| α9, α10 |
α7, α8 |
1 |
2 |
3 |
α1, β1, δ, γ, ε |
| α2, α3, α4, α6 |
β2, β4 |
β3, α5 |
- Alpha genes: (muscle), (neuronal),,,,,,,,
- Beta genes: (muscle), (neuronal),,,
- Other genes: (delta), (epsilon), (gamma)
Notable variations
Nicotinic receptors are pentamers of these subunits, for example each receptor contains five subunits. Thus, there's 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:
Further Information
Get more info on 'Nicotinic'.
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