View source for Nicotinic acetylcholine receptor

{| style="float: right; clear: right; background-color: transparent"
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|[[Image:ACh.png|thumb|[[Acetylcholine]]]]
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|[[Image:Nicotine-2D-skeletal.png|thumb|[[Nicotine]]]]
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|[[Image:Acethylcholine receptor.png|thumb|Acetylcholine receptor (nicotinic) from electric torpedo rays (very similar to human receptor) is made of 5 subunit, 2 of which (shown in orange) binds to ACh (red) (PDB code: 2bg9) ([http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb71_1.html more details...])]]
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|[[Image:Acethylcholine receptor blocked by cobra venom.png|thumb|Acetylcholine receptor blocked by cobra venom (PDB code: 1yi5). A similar effect can be achieved by high doses of curare or nicotine ([http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb71_1.html more details...])]]
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==Overview==

'''Nicotinic acetylcholine receptors''', or '''nAChRs''', are [[ionotropic receptor]]s that form ligand gated [[ion channels]] in [[cell (biology)|cells']] [[plasma membrane]]s. Like the other type of [[acetylcholine receptor]]s, [[muscarinic acetylcholine receptor]]s (mAChRs), their opening is triggered by the [[neurotransmitter]] [[acetylcholine]] (ACh), but they are also opened by [[nicotine]].<ref name="Siegel">Siegel G.J., Agranoff B.W., Fisher S.K., Albers R.W., and Uhler M.D.  1999.  [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 ''Basic Neurochemistry: Molecular, Cellular and Medical Aspects'', Sixth Edition.]  GABA Receptor Physiology and Pharmacology.  American Society for Neurochemistry. Lippincott Williams and Wilkins.  Available.</ref><ref name="Itier">Itier V. and Bertrand D.  2001.  Neuronal nicotinic receptors: from protein structure to function.  Edited by Andreas Engel and Giorgio Semenza. ''FEBS Letters'', 504(3), 118-125. </ref> 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|somatic muscle]]s; stimulation of these receptors causes muscular contraction. 

==Structure==
Nicotinic receptors, with a molecular mass of about 280 [[kilodalton|kDa]],  are made up of five receptor subunits, arranged symmetrically around the central pore. They share similarities with [[GABAA receptor|GABA<sub>A</sub> receptors]], [[glycine receptor]]s, and the type 3 [[serotonin receptor]]s, which are all therefore classed into the ionotropic family, or the signature Cys-loop proteins.<ref name="Cascio">Cascio, M.  2004. [http://www.jbc.org/cgi/content/full/279/19/19383 Structure and function of the glycine receptor and related nicotinicoid receptors.] ''Journal of Biological Chemistry'', 279(19), 19383-19386.  Available.</ref> 

Twelve types of nicotinic receptor subunits, α2 through 10 and β2 through 4 (Itier and Bertrand, 2001), combine to form [[pentamer]]s. The subunits are somewhat similar to one another, especially in the [[hydrophobic]] regions.<ref name="Siegel"> </ref>  The muscle form of the nAChR consist of two α subunits, a β, a δ and either a γ or an ε.<ref name="Siegel"> </ref><ref name="Itier"> </ref><ref name="Giniatullin">Giniatullin R., Nistri A., and Yakel J.L. 2005. Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. ''Trends in Neurosciences'', 28(7), 371-378.</ref>  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-terminal end|N termini]].<ref name="Siegel"> </ref>When the agonist binds, the α subunits become more similar to the other subunits, the channel becomes more symmetrical,<ref name="Colquhoun">Colquhoun D. and Sivilotti L.G. 2004.  Function and structure in glycine receptors and some of their relatives.  ''Trends in Neurosciences'', 27(6), 337-344. </ref> and a pore with a diameter of about 0.65 nm opens.<ref name="Siegel"> </ref>

==Opening the channel==
Nicotinic AChRs may exist in different interconvertible conformational states.  Binding of nicotine stabilizes the open and [[desensitization|desensitised]] states.  Opening of the channel allows positively charged [[ion]]s, in particular, [[sodium]] and [[calcium]], to enter the cell.  

The nAChR is permeable to Na<sup>+</sup> and K<sup>+</sup>, with some subunit combinations that are also permeable to Ca<sup>2+</sup>.<ref name="Siegel"> </ref>  The amount of sodium and potassium the channels allow through their pores (their conductance) is about 25 pS,<ref name="Siegel"> </ref> but the conductance depends on the actual subunit composition. Interestingly, because some neuronal nAChRs are permeable to Ca<sup>2+</sup>, they can affect the release of other neurotransmitters.<ref name="Itier"> </ref> The channel usually opens rapidly and tends to remain open until the [[agonist]] [[diffusion|diffuses]] away, usually for about 1 millisecond.<ref name="Siegel"> </ref>  However, AChRs can open sometimes with only one agonist bound and in rare cases with no agonist bound, and they can close spontaneously even when ACh is bound, so ACh binding only creates a probability of pore opening, which increases as more ACh binds.<ref name="Colquhoun"> </ref>

==Effects==
This activation of receptors by nicotine modifies the state of [[neurons]] through two main mechanisms.  On one hand, the movements of [[cation]]s cause a [[depolarization]] of the plasma membrane, which results in an excitation, particularly of [[neuron]]s, but also by the activation of other [[voltage-gated ion channel]]s.  On the other hand, the entry of calcium acts, either directly or indirectly, on different [[biochemical cascade|intracellular cascades]] leading, for example, to the regulation of the activity of some [[gene]]s or the release of [[neurotransmitters]].

==Roles==
The subunits of the nicotinic receptors belong to a multigene family (16 members in human) and the assembly of combinations of subunits results in a large number of different receptors (For more information see the [http://www.ebi.ac.uk/compneur-srv/LGICdb Ligand Gated Ion Channel database]). These receptors, with highly variable kinetic, [[electrophysiology|electrophysiological]] and [[pharmacology|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.<ref name="Graham">Graham A., Court J.A., Martin-Ruiz C.M., Jaros E., Perry R., Volsen S.G., Bose S., Evans N., Ince P., Kuryatov A., Lindstrom J., Gotti C., and Perry E.K. 2002. Immunohistochemical localisation of nicotinic acetylcholine receptor subunits in human cerebellum. ''Neuroscience'', 113(3), 493-507.</ref>  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.

{| border="1" cellpadding="5" cellspacing="0" style="margin: 1em auto 1em auto;"
|-
| style="text-align: center; background:#66ccff;" colspan="5" | Neuronal-type
| style="text-align: center; background:#ff6666;" | Muscle-type
|-
! style="background:#99cccc;" width="100"| I
! style="background:#66cccc;" width="100"| II
! style="background:#33cccc;" width="300" colspan="3" | III
! style="background:#cc6666;" width="100"| IV
|-
| style="text-align: center;" rowspan="2"| α9, α10
| style="text-align: center;" rowspan="2"| α7, α8
| width="100" style="text-align: center; background:#99ffff;"| 1
| width="100" style="text-align: center; background:#66ffff;"| 2
| width="100" style="text-align: center; background:#33ffff;"| 3
| style="text-align: center;" rowspan="2"| α1, β1, δ, γ, ε
|-
| style="text-align: center;"| α2, α3, α4, α6
| style="text-align: center;"| β2, β4
| style="text-align: center;"| β3, α5
|}

* Alpha genes: {{Gene|CHRNA1}} (muscle), {{Gene|CHRNA2}} (neuronal), {{Gene|CHRNA3}}, {{Gene|CHRNA4}}, {{Gene|CHRNA5}}, {{Gene|CHRNA6}}, {{Gene|CHRNA7}}, {{Gene|CHRNA8}}, {{Gene|CHRNA9}}, {{Gene|CHRNA10}}
* Beta genes: {{Gene|CHRNB1}} (muscle), {{Gene|CHRNB2}} (neuronal), {{Gene|CHRNB3}}, {{Gene|CHRNB4}}, 
* Other genes: {{Gene|CHRND}} (delta), {{Gene|CHRNE}} (epsilon), {{Gene|CHRNG}} (gamma)

==Notable Variations==

===Notable variations=== <!--Ganglion type nicotinic receptor redirects here-->
Nicotinic 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)<sub>2</sub>β1δε (muscle type), (α3)<sub>2</sub>(β4)<sub>3</sub> (ganglion type), (α4)<sub>2</sub>(β2)<sub>3</sub> (CNS type) and (α7)<sub>5</sub> (another CNS type).<ref name=Rang> Pharmacology, (Rang, Dale, Ritter & Moore, ISBN 0443071454, 5:th ed., Churchill Livingstone 2003) Page 138. </ref> A comparison follows:

{| class="wikitable"
|-
! Receptor type !! Location !! Effect !! [[Nicotinic agonists]] !! [[receptor antagonist|Antagonists]]
|-
! [[Muscle type nicotinic receptor|Muscle type]]: <BR> (α1)<sub>2</sub>β1δε<ref name=Rang/> <BR> or <BR> α1β1δγε<ref name=neurosci/> 
| [[Neuromuscular junction]] || [[Excitatory postsynaptic potential|EPSP]], mainly by increased [[sodium|Na<sup>+</sup>]] and [[potassium|K<sup>+</sup>]] permeability || 
*[[acetylcholine]] 
*[[carbachol]] 
*suxamethonium 
|| 
*α-bungarotoxin<ref name=neurosci> [http://www.neurosci.pharm.utoledo.edu/MBC3320/nicotinic.htm Neurosci.pharm - MBC 3320 Acetylcholine] </ref>
*α-conotoxin 
*[[tubocurarine]] 
*[[pancuronium]] 
*[[hexamethonium]] 
|-
! [[Ganglion type nicotinic receptor|Ganglion type]]: <BR> (α1)<sub>2</sub>(β4)<sub>3</sub>
| [[autonomic ganglia]] || [[Excitatory postsynaptic potential|EPSP]], mainly by increased [[sodium|Na<sup>+</sup>]] and [[potassium|K<sup>+</sup>]] permeability || 
* [[acetylcholine]]
*[[carbachol]]
*[[nicotine]]
*[[epibatidine]]
*dimethylphenylpiperazinium
|| 
*α-bungarotoxin<ref name=neurosci/>
*[[mecamylamine]]
*[[trimetaphan]]
|-
! CNS type: <BR> [[alpha-4 beta-2 nicotinic receptor|(α4)<sub>2</sub>(β2)<sub>3</sub>]]
| [[Brain]] || [[Excitatory postsynaptic potential|Post-]] and presynaptic excitation,<ref name=Rang/> mainly by increased [[sodium|Na<sup>+</sup>]] and [[potassium|K<sup>+</sup>]] permeability ||
*[[nicotine]]
*[[epibatidine]]
*[[acetylcholine]]
*[[cytosine]]  
|| 
*[[mecamylamine]]
*methylaconitine
*α-conotoxin
|-
! (another) CNS type: <BR> (α7)<sub>5</sub> <BR> 
| [[Brain]] || [[Excitatory postsynaptic potential|Post-]] and presynaptic excitation,<ref name=Rang/> mainly by increased [[calcium|Ca<sup>2+</sup>]] permeability ||
*[[epibatidine]]
*dimethylphenylpiperazinium
|| 
*[[mecamylamine]]
*α-bungarotoxin
|-
|}

==References==
{{Reflist|2}}

==External links==
*[http://opm.phar.umich.edu/protein.php?pdbid=2bg9 Calculated spatial position of Nicotinic acetylcholine receptor in the lipid bilayer]

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[[Category:Ionotropic receptors]]
[[Category:Neurotransmitters]]
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