title: Desensitization of mutant acetylcholine receptors in transgenic mice reduces the amplitude of neuromuscular synaptic currents.
abstract: While the slow onset of desensitization of nicotinic acetylcholine receptors (AChRs), relative to the rate of acetylcholine removal, excludes this kinetic state from shaping synaptic responses in normal neuromuscular transmission, its role in neuromuscular disorders has not been examined. The slow-channel congenital myasthenic syndrome (SCCMS) is a disorder caused by point mutations in the AChR subunit-encoding genes leading to kinetically abnormal (slow) channels, reduced miniature endplate current amplitudes (MEPCs), and degeneration of the postsynaptic membrane. Because of this complicated picture of kinetic and structural change in the neuromuscular junction, it is difficult to assess the importance of the multiple factors that may be responsible for the reduced endplate current amplitudes, and ultimately the clinical syndrome. In order to address this we have used a transgenic mouse model for the SCCMS that has slow AChR ion channels and reduced endplate responsiveness in the absence of any of the degenerative changes. We found that the reduction in MEPC amplitudes in these mice could not be explained by either reduced AChR number or by reduced AChR channel conductance. Rather, we found that the mutant AChRs in situ manifested an activity-dependent reduction in sensitivity that caused diminished MEPC and endplate current amplitude with nerve stimulation. This observation demonstrates that the basis for the reduction in MEPC amplitudes in the SCCMS may be multifactorial. Moreover, these findings demonstrate that, under conditions that alter their rate of desensitization, the kinetic properties of nicotinic AChRs can control the strength of synaptic responses.
authors.affiliation: Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Bhattacharyya
authors.forename: J W
authors.initials: JW
authors.lastname: Day
authors.forename: J E
authors.initials: JE
authors.lastname: Gundeck
authors.forename: S
authors.initials: S
authors.lastname: Leonard
authors.forename: R L
authors.initials: RL
authors.lastname: Wollmann
authors.forename: C M
authors.initials: CM
authors.lastname: Gomez
mesh_terms: D000818:Animals; D005455:Fluorescent Antibody Technique; D051379:Mice; D008822:Mice, Transgenic; D009045:Motor Endplate / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D011950:Receptors, Cholinergic / Q000235:genetics*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D011950:Receptors, Cholinergic