Novel β subunit mutation causes a slow-channel syndrome by enhancing activation and decreasing the rate of agonist dissociation

Manuel F Navedo, José A. Lasalde-Dominicci, Carlos A. Báez-Pagán, Luzed Díaz-Pérez, Legier V. Rojas, Ricardo A Maselli, Julie Staub, Kelly Schott, Roberto Zayas, Christopher M. Gomez

Research output: Contribution to journalArticle

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Abstract

We traced the cause of a slow-channel syndrome (SCS) in a patient with progressive muscle weakness, repetitive compound muscle action potential and prolonged low amplitude synaptic currents to a V → F substitution in the M1 domain of the β subunit (βV229F) of the muscle acetylcholine receptor (AChR). In vitro expression studies in Xenopus oocytes indicated that the novel mutation βV229F expressed normal amounts of AChRs and decreased the ACh EC50 by 10-fold compared to wild type. Kinetic analysis indicated that the mutation displayed prolonged mean open duration and repeated openings during activation. Prolonged openings caused by the βV229F mutation were due to a reduction in the channel closing rate and an increase in the effective channel opening rate. Repeated openings of the channel during activation were caused by a significant reduction in the agonist dissociation constant. In addition, the βV229F mutation produced an increase in calcium permeability. The kinetic and permeation studies presented in this work are sufficient to explain the consequences of the βV229F mutation on the miniature endplate currents and thus are direct evidence that the βV229F mutation is responsible for compromising the safety margin of neuromuscular transmission in the patient.

Original languageEnglish (US)
Pages (from-to)82-90
Number of pages9
JournalMolecular and Cellular Neuroscience
Volume32
Issue number1-2
DOIs
StatePublished - May 2006

Fingerprint

Mutation
Muscles
Muscle Weakness
Cholinergic Receptors
Xenopus
Action Potentials
Oocytes
Permeability
Calcium
Safety

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Developmental Neuroscience

Cite this

Novel β subunit mutation causes a slow-channel syndrome by enhancing activation and decreasing the rate of agonist dissociation. / Navedo, Manuel F; Lasalde-Dominicci, José A.; Báez-Pagán, Carlos A.; Díaz-Pérez, Luzed; Rojas, Legier V.; Maselli, Ricardo A; Staub, Julie; Schott, Kelly; Zayas, Roberto; Gomez, Christopher M.

In: Molecular and Cellular Neuroscience, Vol. 32, No. 1-2, 05.2006, p. 82-90.

Research output: Contribution to journalArticle

Navedo, MF, Lasalde-Dominicci, JA, Báez-Pagán, CA, Díaz-Pérez, L, Rojas, LV, Maselli, RA, Staub, J, Schott, K, Zayas, R & Gomez, CM 2006, 'Novel β subunit mutation causes a slow-channel syndrome by enhancing activation and decreasing the rate of agonist dissociation', Molecular and Cellular Neuroscience, vol. 32, no. 1-2, pp. 82-90. https://doi.org/10.1016/j.mcn.2006.02.004
Navedo, Manuel F ; Lasalde-Dominicci, José A. ; Báez-Pagán, Carlos A. ; Díaz-Pérez, Luzed ; Rojas, Legier V. ; Maselli, Ricardo A ; Staub, Julie ; Schott, Kelly ; Zayas, Roberto ; Gomez, Christopher M. / Novel β subunit mutation causes a slow-channel syndrome by enhancing activation and decreasing the rate of agonist dissociation. In: Molecular and Cellular Neuroscience. 2006 ; Vol. 32, No. 1-2. pp. 82-90.
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