RGD Reference Report - A highly conserved cytoplasmic cysteine residue in the α4 nicotinic acetylcholine receptor is palmitoylated and regulates protein expression. - Rat Genome Database

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A highly conserved cytoplasmic cysteine residue in the α4 nicotinic acetylcholine receptor is palmitoylated and regulates protein expression.

Authors: Amici, Stephanie A  McKay, Susan B  Wells, Gregg B  Robson, Jordan I  Nasir, Muhammad  Ponath, Gerald  Anand, Rene 
Citation: Amici SA, etal., J Biol Chem. 2012 Jun 29;287(27):23119-27. doi: 10.1074/jbc.M111.328294. Epub 2012 May 16.
RGD ID: 596936208
Pubmed: PMID:22593584   (View Abstract at PubMed)
PMCID: PMC3391155   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M111.328294   (Journal Full-text)

Nicotinic acetylcholine receptor (nAChR) cell surface expression levels are modulated during nicotine dependence and multiple disorders of the nervous system, but the mechanisms underlying nAChR trafficking remain unclear. To determine the role of cysteine residues, including their palmitoylation, on neuronal α4 nAChR subunit maturation and cell surface trafficking, the cysteines in the two intracellular regions of the receptor were replaced with serines using site-directed mutagenesis. Palmitoylation is a post-translational modification that regulates membrane receptor trafficking and function. Metabolic labeling with [(3)H]palmitate determined that the cysteine in the cytoplasmic loop between transmembrane domains 1 and 2 (M1-M2) is palmitoylated. When this cysteine is mutated to a serine, producing a depalmitoylated α4 nAChR, total protein expression decreases, but surface expression increases compared with wild-type α4 levels, as determined by Western blotting and enzyme-linked immunoassays, respectively. The cysteines in the M3-M4 cytoplasmic loop do not appear to be palmitoylated, but replacing all of the cysteines in the loop with serines increases total and cell surface expression. When all of the intracellular cysteines in both loops are mutated to serines, there is no change in total expression, but there is an increase in surface expression. Calcium accumulation assays and high affinity binding for [(3)H]epibatidine determined that all mutants retain functional activity. Thus, our results identify a novel palmitoylation site on cysteine 273 in the M1-M2 loop of the α4 nAChR and determine that cysteines in both intracellular loops are regulatory factors in total and cell surface protein expression of the α4β2 nAChR.




Biological Process

  
Object Symbol
Species
Term
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Evidence
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Original Reference(s)
Chrna4Ratacetylcholine receptor signaling pathway involved_inIDA PMID:22593584UniProt 
Chrna4Ratsynaptic transmission, cholinergic involved_inIDA PMID:22593584UniProt 

Cellular Component

  
Object Symbol
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Term
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Original Reference(s)
Chrna4Ratacetylcholine-gated channel complex part_ofIDA PMID:22593584UniProt 
Chrna4Ratpresynaptic membrane located_inIDA PMID:22593584UniProt 

Molecular Function

  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Chrna4Ratacetylcholine-gated monoatomic cation-selective channel activity enablesIDA PMID:22593584UniProt 


Genes (Rattus norvegicus)
Chrna4  (cholinergic receptor nicotinic alpha 4 subunit)