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Lipid‐protein Interactions Studies in the αC418W Mutant Suffering from Slow Channel Congenital Myasthenic Syndrome
Author(s) -
Grajales Jose Gabriel,
Grajales Gary,
Baez Carlos,
Zhu Haipeng,
Quesada Oreste,
Gomez Christopher,
Lasalde Jose
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb26
Subject(s) - congenital myasthenic syndrome , mutant , acetylcholine receptor , mutation , receptor , nicotinic acetylcholine receptor , microbiology and biotechnology , chemistry , medicine , biology , endocrinology , biochemistry , gene
Cholesterol is known to modulate membrane's biophysical properties and influence function and trafficking of membrane proteins. Cholesterol levels may regulate the movement of membrane proteins from functional to nonfunctional pools. To study this, the nicotinic acetylcholine receptor (nAChR) is used as a model due to its location on a functional pool and also, recent findings indicate that a nAChR mutation (αC418W) displayed an increase in macroscopic response upon cholesterol depletion. The αC418W is the first nAChR mutation identified as cause for a congenital myasthenic syndrome. Using various approaches, we uncovered a fraction of αC418W nAChRs located in caveolin‐positive domains, captive in a non‐functional state and susceptible to cholesterol levels. Cholesterol depletion resulted in the relocation of these receptors to a functional pool. Using a transgenic mouse model bearing the αC418W nAChR, we studied the effects of Lipitor®. After 18 days of statin treatment, the number of nAChRs and the total number of endplates in the diaphragm of the mutant were reduced. As a result, a generalized weakness of the αC418W mutant is present and in some animals an average of 60% loss of spontaneous activity. Understanding the molecular basis for the side‐effects of statins is critical to prevent the collateral contraindications and also to improve therapeutic intervention in hypercholesterolemic patients.