WordNet

the 1st letter of the Roman alphabet (同)a
the blood group whose red cells carry the A antigen (同)type_A, group A
a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response

PrepTutorEJDIC

answer / ampere
=sense organ / 受信装置

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/06/29 12:40:00」(JST)

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Acetylcholine

An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.

Classification

Like other transmembrane receptors, acetylcholine receptors are classified according to their "pharmacology," or according to their relative affinities and sensitivities to different molecules. Although all acetylcholine receptors, by definition, respond to acetylcholine, they respond to other molecules as well.

Nicotinic acetylcholine receptors (nAChR, also known as "ionotropic" acetylcholine receptors) are particularly responsive to nicotine. The nicotine ACh receptor is also a Na+ and K+ ion channel
Muscarinic acetylcholine receptors (mAChR, also known as "metabotropic" acetylcholine receptors) are particularly responsive to muscarine.

Nicotinic and muscarinic are two main kinds of "cholinergic" receptors.

Receptor types

Molecular biology has shown that the nicotinic and muscarinic receptors belong to distinct protein superfamilies.

ACh and its receptors
Drug	Nm	Nn	M1	M2	M3
ACh, Carbachol, Methacholine, AChEi (Psysostigmine, Galantamine, Neostigmine, Pyridostigmine)	+	+	+	+	+
Nicotine, Varenicline	+	+
Succinylcholine	+/-
Atracurium, Vecuronium, Tubocurarine, Pancuronium	-
Epibatidine, DMPP		+
Trimethaphan, Mecamylamine, Bupropion, Dextromethophan, Hexamethonium		-
Muscarine, Oxotremorine, Bethanechol, Pilocarpine			+	+	+
Atropine, Tolterodine, Oxybutynin			-	-	-
Vedaclidine, Talsaclidine, Xanomeline, Ipatropium			+
Pirenzepine, Telenzepine			-
Methoctramin				-
Darifenacin, 4-DAMP, Darifenacin, Solifenacin					-

Nicotinic receptors are of two types: Nm and Nn. Nm is located in the neuromuscular junction which causes the contraction of skeletal muscles by way of end-plate potential (EPPs). Nn causes depolarization in autonomic ganglia resulting in post ganglionic impulse. Nicotinic receptors cause the release of catecholamine from the adrenal medulla, and also site specific excitation or inhibition in brain. Both Nm and Nn are Na + and k + channel linked but Nn is also linked with an extra Ca ++ channel.

nAChR

The nAChRs are ligand-gated ion channels, and, like other members of the "cys-loop" ligand-gated ion channel superfamily, are composed of five protein subunits symmetrically arranged like staves around a barrel. The subunit composition is highly variable across different tissues. Each subunit contains four regions which span the membrane and consist of approximately 20 amino acids. Region II which sits closest to the pore lumen, forms the pore lining. ^[1]

Binding of acetylcholine to the N termini of each of the two alpha subunits results in the 15° rotation of all M2 helices.^[2] The cytoplasm side of the nAChR receptor has rings of high negative charge that determine the specific cation specificity of the receptor and remove the hydration shell often formed by ions in aqueous solution. In the intermediate region of the receptor, within the pore lumen, valine and leucine residues (Val 255 and Leu 251) define a hydrophobic region through which the dehydrated ion must pass.^[3]

The nAChR is found at the edges of junctional folds at the neuromuscular junction on the postsynaptic side; it is activated by acetylcholine release across the synapse. The diffusion of Na⁺ and K⁺ across the receptor causes depolarization, the end-plate potential, that opens voltage-gated sodium channels, which allows for firing of the action potential and potentially muscular contraction.

mAChR

In contrast, the mAChRs are not ion channels, but belong instead to the superfamily of G-protein-coupled receptors that activate other ionic channels via a second messenger cascade. The muscarine cholinergic receptor activates a G-protein when bound to extracellular ACh. The alpha subunit of the G-protein deactivates adenylate cyclase while the beta-gamma subunit activates the K-channels and therefore hyperpolarize the cell. This causes a decrease in cardiac activity.

Role in health and disease

Nicotinic acetylcholine receptors can be blocked by curare, hexamethonium and toxins present in the venoms of snakes and shellfishes, like α-bungarotoxin. Drugs such as the neuromuscular blocking agents bind reversibly to the nicotinic receptors in the neuromuscular junction and are used routinely in anaesthesia.

Nicotinic receptors are the primary mediator of the effects of nicotine. In myasthenia gravis, the receptor at NMJ is targeted by antibodies, leading to muscle weakness. Muscarinic acetylcholine receptors can be blocked by the drugs atropine and scopolamine.

Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in nicotinic acetylcholine receptors. The majority of mutations causing CMS are found in the AChR subunits genes.^[4]

Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult acetylcholine receptor subunits. Mutations of the AChR often result in endplate deficiency. Most of the mutations of the AChR are mutations of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR. ^[5] One type of mutation of the epsilon subunit of the AChR introduces an Arg into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS. ^[6]

References

^ Pohanka, M (2012). "Alpha7 Nicotinic Acetylcholine Receptor Is a Target in Pharmacology and Toxicology". International Journal of Molecular Sciences 13 (2): 2219–2238. doi:10.3390/ijms13022219. PMC 3292018. PMID 22408449.
^ Doyle DA (2004). "Structural changes during ion channel gating". Trends Neurosci. 27 (6): 298–302. doi:10.1016/j.tins.2004.04.004. PMID 15165732.
^ Miyazawa A, Fujiyoshi Y, Unwin N (2003). "Structure and gating mechanism of the acetylcholine receptor pore". Nature 423 (6943): 949–55. doi:10.1038/nature01748. PMID 12827192.
^ Cossins, J.; Burke, G.; Maxwell, S.; Spearman, H.; Man, S.; Kuks, J.; Vincent, A.; Palace, J.; Fuhrer, C.; Beeson, D. (2006). "Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations". Brain 129 (10): 2773–2783. doi:10.1093/brain/awl219. PMID 16945936. edit
^ Abicht, A.; Dusl, M.; Gallenmüller, C.; Guergueltcheva, V.; Schara, U.; Della Marina, A.; Wibbeler, E.; Almaras, S.; Mihaylova, V.; Von Der Hagen, M.; Huebner, A.; Chaouch, A.; Müller, J. S.; Lochmüller, H. (2012). "Congenital myasthenic syndromes: Achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: A study of 680 patients". Human Mutation 33 (10): 1474–1484. doi:10.1002/humu.22130. PMID 22678886. edit
^ Shen, X. -M.; Brengman, J. M.; Edvardson, S.; Sine, S. M.; Engel, A. G. (2012). "Highly fatal fast-channel syndrome caused by AChR subunit mutation at the agonist binding site". Neurology 79 (5): 449–454. doi:10.1212/WNL.0b013e31825b5bda. PMC 3405251. PMID 22592360. edit

External links

Acetylcholine receptor: PMAP The Proteolysis Map-animation
Acetylcholine Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
Acetlycholine Receptor: Molecule of The Month by David Goodsell
Acetylcholine receptors: muscarinic and nicotinic by Flavio Guzman
ANS receptors-overview

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English Journal

Cholinergic antagonist 3-quinuclidinyl benzilate - Impact on learning and memory in Wistar rats.

Misik J1, Vanek J2, Musilek K3, Kassa J3.Author information 1Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Electronic address: misik@pmfhk.cz.2Department of Public Health, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.3Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.Abstract3-Quinuclidinyl benzilate (QNB) represents a non-selective, competitive antagonist of cholinergic receptors, which has been previously used to generate cognitive deficits in animal models of neurodegenerative disorders. The aim of this study was evaluation of QNB potency for creation of cognitive impairment during the acquisition, consolidation and retrieval stages of learning and memory in rats. Male Wistar rats were subjected to a water maze task with hidden platform and a step-through passive avoidance task. The water maze test was carried out in two separate experiments focused on spatial learning (acquisition test) and long-term spatial memory (retrieval test). QNB doses (0.5, 1.0, 2.0 and 5.0mgkg(-1)) were administered to rats intraperitoneally before training sessions (acquisition test) or before probe trial (retrieval test). A QNB dose of 2.0mgkg(-1) was administered to rats in the passive avoidance task before training (acquisition test), immediately post-training (consolidation test) or 24h pre-retention (retrieval test). QNB significantly impaired the acquisition in the water maze at doses 0.5-5.0mgkg(-1) as well as the acquisition of passive avoidance task. In contrast, consolidation and retrieval were not affected by QNB, indicating that QNB specifically affects the stage of acquisition.
Behavioural brain research.Behav Brain Res.2014 Jun 1;266:193-200. doi: 10.1016/j.bbr.2014.03.001. Epub 2014 Mar 13.
3-Quinuclidinyl benzilate (QNB) represents a non-selective, competitive antagonist of cholinergic receptors, which has been previously used to generate cognitive deficits in animal models of neurodegenerative disorders. The aim of this study was evaluation of QNB potency for creation of cognitive im
PMID 24632008

Differential effects of genetically-encoded Gβγ scavengers on receptor-activated and basal Kir3.1/Kir3.4 channel current in rat atrial myocytes.

Kienitz MC1, Mintert-Jancke E2, Hertel F2, Pott L2.Author information 1Institute of Physiology, Ruhr-University Bochum, D-44780 Bochum, Germany. Electronic address: cecile.kienitz@rub.de.2Institute of Physiology, Ruhr-University Bochum, D-44780 Bochum, Germany.AbstractOpening of G-protein-activated inward-rectifying K(+) (GIRK, Kir3) channels is regulated by interaction with βγ-subunits of Pertussis-toxin-sensitive G proteins upon activation of appropriate GPCRs. In atrial and neuronal cells agonist-independent activity (Ibasal) contributes to the background K(+) conductance, important for stabilizing resting potential. Data obtained from the Kir3 signaling pathway reconstituted in Xenopus oocytes suggest that Ibasal requires free Gβγ. In cells with intrinsic expression of Kir3 channels this issue has been scarcely addressed experimentally. Two Gβγ-binding proteins (myristoylated phosducin - mPhos - and Gαi1) were expressed in atrial myocytes using adenoviral gene transfer, to interrupt Gβγ-signaling. Agonist-induced and basal currents were recorded using whole cell voltage-clamp. Expression of mPhos and Gαi1 reduced activation of Kir3 current via muscarinic M2 receptors (IK(ACh)). Inhibition of IK(ACh) by mPhos consisted of an irreversible component and an agonist-dependent reversible component. Reduction in density of IK(ACh) by overexpressed Gαi1, in contrast to mPhos, was paralleled by substantial slowing of activation, suggesting a reduction in density of functional M2 receptors, rather than Gβγ-scavenging as underlying mechanism. In line with this notion, current density and activation kinetics were rescued by fusing the αi1-subunit to an Adenosine A1 receptor. Neither mPhos nor Gαi1 had a significant effect on Ibasal, defined by the inhibitory peptide tertiapin-Q. These data demonstrate that basal Kir3 current in a native environment is unrelated to G-protein signaling or agonist-independent free Gβγ. Moreover, our results illustrate the importance of physiological expression levels of the signaling components in shaping key parameters of the response to an agonist.
Cellular signalling.Cell Signal.2014 Jun;26(6):1182-92. doi: 10.1016/j.cellsig.2014.02.007. Epub 2014 Feb 24.
Opening of G-protein-activated inward-rectifying K(+) (GIRK, Kir3) channels is regulated by interaction with βγ-subunits of Pertussis-toxin-sensitive G proteins upon activation of appropriate GPCRs. In atrial and neuronal cells agonist-independent activity (Ibasal) contributes to the background K(
PMID 24576551

M2 receptors exert analgesic action on DRG sensory neurons by negatively modulating VR1 activity.

De Angelis F1, Marinelli S, Fioretti B, Catacuzzeno L, Franciolini F, Pavone F, Tata AM.Author information 1Department of Biology and Biotechnologies C. Darwin, "Sapienza" University of Rome, Rome, Italy.AbstractThe peripheral application of the M2 cholinergic agonist arecaidine on sensory nerve endings shows anti-nociceptive properties. In this work, we analyze in vitro, the mechanisms downstream M2 receptor activation causing the analgesic effects, and in vivo the effects produced by M2 agonist arecaidine administration on nociceptive responses in a murine model of nerve growth factor (NGF)-induced pain. Cultured DRG neurons treated with arecaidine showed a decreased level of VR1 and SP transcripts. Conversely, we found an increased expression of VR1 and SP transcripts in DRG from M2/M4(-/-) mice compared to WT and M1(-/-) mice, confirming the inhibitory effect in particular of M2 receptors on SP and VR1 expression. Patch-clamp experiments in the whole-cell configuration showed that arecaidine treatment caused a reduction of the fraction of capsaicin-responsive cells, without altering the mean capsaicin-activated current in responsive cells. We also demonstrated that arecaidine prevents PKCϵ translocation to the plasma membrane after inflammatory agent stimulation, mainly in medium-small sensory neurons. Finally, in mice, we have observed that intraperitoneal injection of arecaidine reduces VR1 expression blocking hyperalgesia and allodynia caused by NGF intraplantar administration. In conclusion, our data demonstrate that in vivo M2 receptor activation induces desensitization to mechanical and heat stimuli by a down-regulation of VR1 expression and by the inhibition of PKCϵ activity hindering its translocation to the plasma membrane, as suggested by in vitro experiments.
Journal of cellular physiology.J Cell Physiol.2014 Jun;229(6):783-90. doi: 10.1002/jcp.24499.
The peripheral application of the M2 cholinergic agonist arecaidine on sensory nerve endings shows anti-nociceptive properties. In this work, we analyze in vitro, the mechanisms downstream M2 receptor activation causing the analgesic effects, and in vivo the effects produced by M2 agonist arecaidine
PMID 24166293