Potential role of caveolin-1-positive domains in the regulation of the acetylcholine receptor's activatable pool: implications in the pathogenesis of a novel congenital myasthenic syndrome.
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 (alpha C418W) that produces a congenital myasthenic syndrome (CMS), demonstrated that cholesterol depletion causes a remarkable increase in the alpha C418W 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 alpha C418W nAChR's macroscopic current. The present study suggests that a substantial fraction of the alpha C418W 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 alpha C418W 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 alpha C418W nAChR.
Báez-Pagán
Carlos A
CA
Department of Chemistry, University of Puerto Rico-Rio Piedras, San Juan, Puerto Rico.
Martínez-Ortiz
Yaiza
Y
Otero-Cruz
José D
JD
Salgado-Villanueva
Iris K
IK
Velázquez
Guermarie
G
Ortiz-Acevedo
Alejandro
A
Quesada
Orestes
O
Silva
Walter I
WI
Lasalde-Dominicci
José A
JA
D000818:Animals; D051242:Caveolin 1 / Q000096:biosynthesis*; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D021962:Membrane Microdomains; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013577:Syndrome; D014101:Torpedo; D014982:Xenopus laevis / Q000378:metabolism
D051242:Caveolin 1; D011978:Receptors, Nicotinic; D002784:Cholesterol