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 language | English (US) |
|---|---|
| Pages (from-to) | 82-90 |
| Number of pages | 9 |
| Journal | Molecular and Cellular Neuroscience |
| Volume | 32 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - May 2006 |
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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 journal › Article
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TY - JOUR
T1 - Novel β subunit mutation causes a slow-channel syndrome by enhancing activation and decreasing the rate of agonist dissociation
AU - Navedo, Manuel F
AU - Lasalde-Dominicci, José A.
AU - Báez-Pagán, Carlos A.
AU - Díaz-Pérez, Luzed
AU - Rojas, Legier V.
AU - Maselli, Ricardo A
AU - Staub, Julie
AU - Schott, Kelly
AU - Zayas, Roberto
AU - Gomez, Christopher M.
PY - 2006/5
Y1 - 2006/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33744970023&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33744970023&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2006.02.004
DO - 10.1016/j.mcn.2006.02.004
M3 - Article
C2 - 16624571
AN - SCOPUS:33744970023
VL - 32
SP - 82
EP - 90
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
SN - 1044-7431
IS - 1-2
ER -