Desensitization of the nicotinic acetylcholine receptor: Molecular mechanisms and effect of modulators

1989 ◽  
Vol 9 (2) ◽  
pp. 141-178 ◽  
Author(s):  
Enrique L. M. Ochoa ◽  
Amitabha Chattopadhyay ◽  
Mark G. McNamee
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Molecular Mechanisms ◽  
Nicotinic Acetylcholine

scholarly journals Caveolin-3 Promotes Nicotinic Acetylcholine Receptor Clustering and Regulates Neuromuscular Junction Activity

2010 ◽  
Vol 21 (2) ◽  
pp. 302-310 ◽  
Author(s):  
Michael Hezel ◽  
William C. de Groat ◽  
Ferruccio Galbiati
Keyword(s):  
Neuromuscular Junction ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
Structural Protein ◽  
Receptor Clustering ◽  
Nicotinic Acetylcholine ◽  
Functional Studies ◽  
Muscle Specific Kinase

The molecular mechanisms that regulate the organization and activity of the neuromuscular junction remain to be fully identified. Caveolae are invaginations of the plasma membrane. Caveolin-3 is the structural protein component of caveolae in muscle cells. We show that caveolin-3 is expressed at the neuromuscular junction, that it associates with the nicotinic acetylcholine receptor (nAChR), and that a lack of caveolin-3 inhibits clustering of the nAChR in myotubes. At the molecular level, we demonstrate that caveolin-3 is a novel muscle-specific kinase (MuSK) binding protein and that altered nAChR clustering in caveolin-3–lacking myotubes results from inhibition of agrin-induced phosphorylation/activation of MuSK and activation of Rac-1. Functional studies in caveolin-3 null mice show abnormal neuromuscular junction activity that is consistent with altered nAChR localization at the sarcolemma. Together, these data identify caveolin-3 as a critical component of the signaling machinery that drives nicotinic acetylcholine receptor clustering and controls neuromuscular junction function.

Molecular mechanisms of reduced β-adrenergic signaling in the aged heart as revealed by genomic profiling

2003 ◽  
Vol 15 (2) ◽  
pp. 142-147 ◽  
Author(s):  
James G. Dobson ◽  
John Fray ◽  
Jack L. Leonard ◽  
Richard E. Pratt
Keyword(s):  
Gene Expression ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Adrenergic Receptor ◽  
Molecular Mechanisms ◽  
Statistical Significance ◽  
Male Rats ◽  
Nicotinic Acetylcholine ◽  
Adrenergic Signaling ◽  
Age Related

Myocardial aging leads to a reduction of β-adrenergic receptor-induced metabolic and contractile responsiveness. We hypothesize that a change in the patterns of gene expression is important in these age-related events. To test this, hearts were harvested from young and aged male rats (3–4 and 20–22 mo, respectively). Total mRNA was extracted and prepared for hybridization to Affymetrix U34A GeneChips. Filtering criteria, involving fold change and a statistical significance cutoff were employed, yielding 263 probe pairs exhibiting differential signals. Of the 163 annotated genes, at least 56 (34%) were classified as signaling/cell communication. Of these 56, approximately half were directly involved in G protein-coupled receptor signaling pathways. We next determined which of these changes might be involved in anti-adrenergic activity and identified 19 potentially important gene products. Importantly, we observed a decrease in β1-adrenergic receptor and adenylyl cyclase mRNAs, whereas the mRNA encoding β-arrestin increased. Furthermore, the results demonstrate an increase in mRNAs encoding the adenosine A1 receptor and phospholipase D, which could increase anti-adrenergic effects. Moreover, the mRNAs encoding the muscarinic M3 receptor, nicotinic acetylcholine receptor β3, and nicotinic acetylcholine receptor-related protein were increased as was the mRNA encoding guanylate kinase-associated protein. Interestingly, we also observed eight mRNAs whose abundance changed three- to sixfold with aging that could be considered as being compensatory. Although these results do not prove causality, they demonstrate that cardiac aging is associated with changes in the profiles of gene expression and that many of these changes may contribute to reduced adrenergic signaling.

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