title: Mutation of single murine acetylcholine receptor subunits reveals differential contribution of P121 to acetylcholine binding and channel opening.
abstract: The nicotinic acetylcholine receptor (AChR) is a heteropentameric, ligand-gated ion channel at the neuromuscular junction, where it is responsible for signal transduction between the motorneuron and the muscle. Point mutations in the subunits of the receptor change the channel's electrophysiological properties and underlie inherited forms of muscle weakness, the congenital myasthenic syndromes. One point mutation (P121L) has been identified in the epsilon-subunit of patients suffering from the fast-channel congenital myasthenic syndrome, which is evoked by reduced AChR openings. We introduced the P121L mutation into all murine AChR subunits and performed electrophysiological studies in Xenopus laevis oocytes. The P121L mutation in the epsilon-subunit of the adult mouse AChR affected ligand binding and channel gating in a manner similar to that described for human AChR. At equivalent positions in the alpha- and beta-subunits, the mutation caused only minor electrophysiological changes. Mutation of the delta-subunit had similar, but less pronounced functional consequences compared to epsilonP121L, reflecting the asymmetry of the acetylcholine binding sites and the dominant effect of the alpha-epsilon site on channel opening.
authors.affiliation: Abt. Zellphysiologie, Max-Planck-Institut für medizinische Forschung, Jahnstr. 29, 69120, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Peter
authors.forename: Alon
authors.initials: A
authors.lastname: Korngreen
authors.forename: Veit
authors.initials: V
authors.lastname: Witzemann
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism; D006801:Humans; D051379:Mice; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D011392:Proline / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D014982:Xenopus laevis
chemical_list: D002038:Bungarotoxins; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D011392:Proline; D000109:Acetylcholine