Page last updated: 2024-10-24

positive regulation of skeletal muscle acetylcholine-gated channel clustering

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of skeletal muscle acetylcholine-gated channel clustering. [GO_REF:0000058, GOC:TermGenie, PMID:7722643]

Positive regulation of skeletal muscle acetylcholine-gated channel clustering is a complex biological process that ensures the proper formation and function of neuromuscular junctions (NMJs). NMJs are specialized synapses where motor neurons transmit signals to skeletal muscle fibers, initiating muscle contraction. Acetylcholine-gated channels, also known as nicotinic acetylcholine receptors (nAChRs), are located at the postsynaptic membrane of the muscle fiber and are essential for receiving and responding to acetylcholine released from the motor neuron.

The clustering of nAChRs at the postsynaptic membrane is crucial for efficient neurotransmission. This process involves several key steps:

1. **Initial Aggregation:** The first step is the aggregation of nAChRs at the nascent synapse. This is mediated by the interaction of the cytoplasmic domains of nAChR subunits with specific adaptor proteins, such as rapsyn. Rapsyn acts as a scaffold protein, linking nAChRs to the cytoskeleton and facilitating their clustering.

2. **Synaptic Stabilization:** Once nAChRs are clustered, they are stabilized at the synapse by interactions with other proteins, including agrin, MuSK, and LRP4. Agrin is a protein secreted from the motor neuron that binds to LRP4 and MuSK, which are transmembrane receptors located at the muscle fiber membrane. This interaction triggers a signaling cascade that activates MuSK, a tyrosine kinase, and leads to the phosphorylation of various proteins, including rapsyn. Phosphorylation of rapsyn enhances its ability to bind and cluster nAChRs.

3. **Signal Transduction:** The signaling pathway triggered by agrin-MuSK interaction is essential for the proper clustering and maintenance of nAChRs. This pathway involves multiple signaling molecules, including kinases, phosphatases, and adaptor proteins. These molecules cooperate to regulate the phosphorylation state of various proteins involved in nAChR clustering and synaptic organization.

4. **Feedback Regulation:** The clustering of nAChRs at the synapse also influences the release of acetylcholine from the motor neuron. This is achieved through a feedback loop involving a protein called neuregulin. Neuregulin is secreted from the muscle fiber and binds to ErbB receptors on the motor neuron, triggering the release of acetylcholine. This feedback loop ensures that the amount of acetylcholine released matches the number of nAChRs at the synapse, thereby optimizing neurotransmission.

5. **Dynamic Regulation:** The clustering of nAChRs is not static but is constantly regulated by factors such as muscle activity and environmental cues. Muscle activity, for example, can influence the stability and size of nAChR clusters. Environmental cues, such as growth factors and neurotrophic factors, can also modulate nAChR clustering.

In summary, the positive regulation of skeletal muscle acetylcholine-gated channel clustering is a complex and tightly regulated process that involves multiple molecular interactions and signaling pathways. This process is essential for the proper formation and function of NMJs, ensuring efficient communication between motor neurons and muscle fibers, and ultimately enabling coordinated muscle contraction.'
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Proteins (1)

ProteinDefinitionTaxonomy
Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alphaA protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha that is encoded in the genome of human. [PRO:DNx, UniProtKB:P49354]Homo sapiens (human)

Compounds (30)

CompoundDefinitionClassesRoles
1,10-phenanthroline1,10-phenanthroline: RN given refers to parent cpd; inhibits Zn-dependent metalloproteinasesphenanthrolineEC 2.7.1.1 (hexokinase) inhibitor;
EC 3.4.19.3 (pyroglutamyl-peptidase I) inhibitor
2,2'-dipyridyl2,2'-bipyridine : A bipyridine in which the two pyridine moieties are linked by a bond between positions C-2 and C-2'.

2,2'-Dipyridyl: A reagent used for the determination of iron.
bipyridinechelator;
ferroptosis inhibitor
ethylenediamineethylenediamine : An alkane-alpha,omega-diamine in which the alkane is ethane.

ethylenediamine: RN given refers to parent cpd; edamine is the recommended contraction for the ethylenediamine radical
alkane-alpha,omega-diamineGABA agonist
cortisone acetateCortisone Acetate: The acetate ester of cortisone that is used mainly for replacement therapy in adrenocortical insufficiency and in the treatment of many allergic and inflammatory disorders.corticosteroid hormone
gliotoxingliotoxin : A pyrazinoindole with a disulfide bridge spanning a dioxo-substituted pyrazine ring; mycotoxin produced by several species of fungi.

Gliotoxin: A fungal toxin produced by various species of Trichoderma, Gladiocladium fimbriatum, Aspergillus fumigatus, and Penicillium. It is used as an immunosuppressive agent.
dipeptide;
organic disulfide;
organic heterotetracyclic compound;
pyrazinoindole
antifungal agent;
EC 2.5.1.58 (protein farnesyltransferase) inhibitor;
immunosuppressive agent;
mycotoxin;
proteasome inhibitor
sch 37370N-acetyldesloratadine: dual antagonist of platelet-activating factor and histamine
desloratadinedesloratadine : Loratadine in which the ethoxycarbonyl group attached to the piperidine ring is replaced by hydrogen. The major metabolite of loratidine, desloratadine is an antihistamine which is used for the symptomatic relief of allergic conditions including rhinitis and chronic urticaria. It does not readily enter the central nervous system, so does not cause drowsiness.

desloratadine: major metabolite of loratadine
benzocycloheptapyridineanti-allergic agent;
cholinergic antagonist;
drug metabolite;
H1-receptor antagonist
b 581B 581 : A dipeptide obtained from the tetrapeptide Cys-Val-Phe-Met by reduction of the amide carbonyl groups of the Cys and Val residues.

B 581: blocks farnesylated but not geranylgeranylated or myristylated, oncogenic Ras signaling & transformation
dipeptideEC 2.5.1.58 (protein farnesyltransferase) inhibitor;
peptidomimetic
r115777
lonafarniblonafarnib : A 4-{2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl}piperidine-1-carboxamide that has R configuration. It is used as oral farnesyltransferase inhibitor.

lonafarnib: inhibitor of farnesyl protein transferase
4-{2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl}piperidine-1-carboxamideantineoplastic agent;
EC 2.5.1.58 (protein farnesyltransferase) inhibitor
tipifarnibimidazoles;
monochlorobenzenes;
primary amino compound;
quinolone
antineoplastic agent;
apoptosis inducer;
EC 2.5.1.58 (protein farnesyltransferase) inhibitor
l 778,123L-778,123 (free base) : A member of the class of imidazoles that is 1H-imidazole substituted by (4-cyanophenyl)methyl and [4-(3-chlorophenyl)-3-oxopiperazin-1-yl]methyl groups at positions 1 and 5, respectively. It is a dual inhibitor of FPTase and GGPTase-I.imidazoles;
monochlorobenzenes;
nitrile;
piperazinone;
tertiary amino compound
antineoplastic agent;
EC 2.5.1.58 (protein farnesyltransferase) inhibitor;
EC 2.5.1.59 (protein geranylgeranyltransferase type I) inhibitor
halenaquinonehalenaquinone: RN given refers to (S)-isomer; structure in first source
fti 276FTI 276: a ras CAAX (C - Cys; A - aliphatic amino acid; X - Ser or Met) peptidomimetic; inhibits farnesyltransferase; FTI-277 is the methyl ester derivative of FTI-276methionine derivative
lb42908LB42908 : A member of the class of pyrrolecarboxamides that is 1H-pyrrole substituted by [1-(3a,7a-dihydro-1,3-benzodioxol-5-ylmethyl)-1H-imidazol-5-yl]methyl, (4-methylpiperazin-1-yl)carbonyl, and naphthalen-1-yl groups at positions 1, 3 and 4, respectively. It is a potent inhibitor of Ras farnesyltransferase (IC50= 0.9nM against H-Ras and 2.4nM against K-Ras) with potential anticancer activity.

LB42908: structure in first source
farnesyl pyrophosphate2-trans,6-trans-farnesyl diphosphate : The trans,trans-stereoisomer of farnesyl diphosphate.

farnesyl pyrophosphate: a sesquiterpene that dimerizes to SQUALENE; RN given refers to cpd without isomeric designation
farnesyl diphosphateEscherichia coli metabolite;
mouse metabolite
a 228839A 228839: an immunosuppressive agent; structure in first source
bms 2146627-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine: a farnesyltransferase inhibitor; structure in first source

BMS-214662 : A member of the class of benzodiazepines that is 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine substituted by (1H-imidazol-5-yl)methyl, benzyl, (thiophen-2-yl)sulfonyl, and cyano groups at positions 1, 3R, 4 and 7, respectively. It is a potent inhibitor of farnesyltransferase (IC50 = 1.35nM) which was under clinical development for the treatment of solid tumors.
benzenes;
benzodiazepine;
imidazoles;
nitrile;
sulfonamide;
thiophenes
antineoplastic agent;
apoptosis inducer;
EC 2.5.1.58 (protein farnesyltransferase) inhibitor
fti 277
ggti 286GGTI 286: the methyl ester of GGTI-287; inhibits geranylgeranyltransferase
chaetomellic acid achaetomellic acid A: structure given in first source; an inhibitor of farnesyl-protein transferase
kurasoin akurasoin A: protein farnesyltransferase inhibitor; isolated from Paecilomyces; structure in first source
kurasoin bkurasoin B: protein farnesyltransferase inhibitor; isolated from Paecilomyces; structure in first source
manumycinmanumycin A : A polyketide with formula C31H38N2O7 initially isolated from Streptomyces parvulus as a result of a random screening program for farnesyl transferase (FTase) inhibitors. It is a natural product that exhibits anticancer and antibiotic properties.

manumycin: an NSAID; RN given for (1S-(1alpha,3(2E,4E,6S*),5alpha,5(1E,3E,5E),6alpha))-isomer; a farnesyl protein transferase inhibitor; from Streptomyces parvulus; MF C31-H38-N2-O7; structure given in first source
enamide;
epoxide;
organic heterobicyclic compound;
polyketide;
secondary carboxamide;
tertiary alcohol
antiatherosclerotic agent;
antimicrobial agent;
antineoplastic agent;
apoptosis inducer;
bacterial metabolite;
EC 1.8.1.9 (thioredoxin reductase) inhibitor;
EC 2.5.1.58 (protein farnesyltransferase) inhibitor;
marine metabolite
clavaric acidclavaric acid: inhibits farnesyl-protein transferase; isolated from Clavariadelphus truncatus; structure in first source
ggti 298GGTI 298: inhibits geranylgeranyltransferase-I; structure in first sourceleucine derivative
sch 44342SCH 44342: inhibits farnesyl protein transferase; structure in first source
lb42708LB42708: farnesyltransferase inhibitor; structure in first source
actinoplanic acid aactinoplanic acid A: isolated from Actinoplanes; inhibits farnesyl-protein transferase; structure in first source
moverastin amoverastin A: inhibits cancer cell migration; isolated from Aspergillus; structure in first source