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Research Papers

Potential role of caveolin-1-positive domains in the regulation of the acetylcholine receptor's activable pool: Implications in the pathogenesis of a novel congenital myasthenic syndrome

Carlos Baez, Yaiza Martinez-Ortiz, Jose D. Otero-Cruz, Iris K. Salgado-Villanueva, Guermarie Velazquez, Alejandro Ortiz-Acevedo, Orestes Quesada, Walter I. Silva and José A. Lasalde-Dominicci

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Cholesterol modulates the plasmalemma's biophysical properties and influences the function and trafficking of membrane proteins. A fundamental phenomenon that remains obscure is how the plasmalemma's lipid composition regulates the activatable pool of membrane receptors. An outstanding model to study this phenomenon is the nicotinic acetylcholine receptor (nAChR), since the nAChR activatable pool has been estimated to be but a small fraction of the receptors present in the plasmalemma. Studies on the effect of cholesterol depletion in the function of the Torpedo californica nAChR, using the lipid-exposed nAChR mutation (αC418W) that produces a congenital myasthenic syndrome (CMS), demonstrated that cholesterol depletion causes a remarkable increase in the αC418W nAChR's macroscopic current whereas not in the wild type (WT). A variety of approaches were used to define the mechanism responsible for the cholesterol depletion mediated-increase in the αC418W nAChR's macroscopic current. The present study suggests that a substantial fraction of the αC418W nAChRs is located in caveolin-1-positive domains, "trapped" in a non-activatable state, and that membrane cholesterol depletion results in the relocation of these receptors to the activatable pool. Co-fractionation and co-immunoprecipitation of the αC418W nAChR and the membrane raft protein caveolin-1 (cav1) support the notion that interactions at lipid-exposed domains regulate the partition of the receptor into membrane raft microdomains. These results have potential implications as a novel mechanism to fine-tune cholinergic transmission in the nervous system and in the pathogenesis associated to the αC418W nAChR.

Authors

Carlos Baez

University of Puerto Rico

Yaiza Martinez-Ortiz

University of Puerto Rico

Jose D. Otero-Cruz

University of Puerto Rico

Iris K. Salgado-Villanueva

University of Puerto Rico

Guermarie Velazquez

University of Puerto Rico

Alejandro Ortiz-Acevedo

University of Puerto Rico

Orestes Quesada

University of Puerto Rico

Walter I. Silva

University of Puerto Rico

José A. Lasalde-Dominicci

University of Puerto Rico

Purchase article for $19

Subscribe to this journal for $79/year