Postsynaptic Development of the Neuromuscular Junction in Mice Lacking the γ-Subunit of Muscle Nicotinic Acetylcholine Receptor

Liu, Yun; Sugiura, Yoshie; Padgett, Daniel; Lin, Weichun

doi:10.1007/s12031-009-9248-x

Cited by 13 publications

(9 citation statements)

References 37 publications

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“…The absence of AChR clusters was associated with excessive nerve branching, increased motoneuron survival, and aberrant distribution of the NMJ components AChE and rapsyn [Liu et al, ]. At E18.5, after the γ‐ to ϵ‐subunit switch occurred, the size of the endplate was larger in the mutant than wild type, but the fluorescence intensity of AChR staining was diminished, suggesting a decrease in the density of AChRs [Liu et al, ]. These results demonstrate that the γ‐subunit is required for the assembly of AChR clusters, which in turn play a role in the assembly of the postsynaptic apparatus at the NMJ.…”

Section: Discussionmentioning

confidence: 99%

Neuromotor synapses in Escobar syndrome

Robinson

Viereck

Margiotta

et al. 2013

American J of Med Genetics Pt A

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The Escobar variant of multiple pterygium syndrome (OMIM #265000) is a rare, autosomal recessive disorder associated with mutations in the γ-subunit of the nicotinic acetylcholine receptor (CHRNG). CHRNG is expressed in fetal muscle during motor development and contributes to the formation of neuromuscular junctions. Anomalies in neuromuscular junction structure and function have not been investigated in patients with Escobar syndrome. We report five patients identified as having Escobar syndrome, from four families. In three families, the same mutation (c.459dupA) was identified in CHRNG. A biopsy from brachioradialis muscle was collected from a patient from one of these families and analyzed for neuromuscular junction organization using fluorescence microscopy. Compared to spinalis muscle from control patients with idiopathic scoliosis or cerebral palsy, the patient with Escobar syndrome had a significantly higher degree of acetylcholine receptor present outside acetylcholinesterase; and significantly less acetylcholinesterase outside acetylcholine receptor. Given the role of the acetylcholine receotor γ-subunit in fetal neuromuscular signal transduction and in establishing the primary encounter of muscle and motor nerve terminal, the CHRNG mutation described in Escobar syndrome may cause a broader disruption of postsynaptic proteins and result in aberrant development of the NMJ due to impaired prenatal neuromuscular transmission and/or abnormal neuromuscular synaptogenesis.

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Section: Discussionmentioning

confidence: 99%

Neuromotor synapses in Escobar syndrome

Robinson

Viereck

Margiotta

et al. 2013

American J of Med Genetics Pt A

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“…Robinson et al previously reported a case where non‐colocalization of NMJ proteins was also detected (Robinson et al, ). These postnatal abnormalities at the NMJ probably reflect the developmental effects of impaired prenatal neuromuscular transmission as well as an aberrant neuromuscular synaptogenesis (Liu et al, ; Liu, Sugiura, Padgett, & Lin, ).…”

Section: Discussionmentioning

confidence: 99%

CHRNG‐related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical, histopathological, and molecular genetic findings

Carrera‐García

Benito

Dieterich³

et al. 2019

American J of Med Genetics Pt A

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Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS).Herein we present a long-term follow-up of seven patients with CHRNG-related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics, but also the type and degree of muscle involvement on whole-body magnetic resonance imaging (WBMRI). CHRNG mutations lead to a distinctive phenotype characterized by multiple congenital contractures, pterygium, and facial dysmorphism, with a stable clinical course over the years. Postnatal abnormalities at the neuromuscular junction were observed in the muscle biopsy of these patients.Laura Carrera-García and Daniel Natera-de Benito contributed equally to this study.

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“…Without γ-subunit, neuromuscular synapses do not develop properly (3) and are abnormal in innervation patterns (4) and muscle fiber-type composition (5). In mice, the γ-subunit KO is lethal (6), and in humans, mutations in the cholinergic receptor, nicotinic, gamma (CHRNG) gene that encodes for γ-subunit are associated with lethal forms of multiple pterygium and Escobar syndromes (7)(8)(9).…”

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confidence: 99%

Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response

Nayak

Auerbach

2013

Proc. Natl. Acad. Sci. U.S.A.

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Neuromuscular acetylcholine receptors (AChRs) have two transmitter binding sites: at α−δ and either α−γ (fetal) or α-e (adult) subunit interfaces. The γ-subunit of fetal AChRs is indispensable for the proper development of neuromuscular synapses. We estimated parameters for acetylcholine (ACh) binding and gating from single channel currents of fetal mouse AChRs expressed in tissuecultured cells. The unliganded gating equilibrium constant is smaller and less voltage-dependent than in adult AChRs. However, the α−γ binding site has a higher affinity for ACh and provides more binding energy for gating compared with α−e; therefore, the diliganded gating equilibrium constant at −100 mV is comparable for both receptor subtypes. The −2.2 kcal/mol extra binding energy from α−γ compared with α−δ and α−e is accompanied by a higher resting affinity for ACh, mainly because of slower transmitter dissociation. End plate current simulations suggest that the higher affinity and increased energy from α−γ are essential for generating synaptic responses at low pulse [ACh].are ligand-gated ion channels comprised of five subunits: two α(1) and one each of β, δ, and either γ or e. In most species, the γ-subunit is replaced by e during postnatal development. Electrical activity in muscle cells induced by the neurotransmitter acetylcholine (ACh) is important for the molecular maturation of γ-to e-AChRs (1, 2).Without γ-subunit, neuromuscular synapses do not develop properly (3) and are abnormal in innervation patterns (4) and muscle fiber-type composition (5). In mice, the γ-subunit KO is lethal (6), and in humans, mutations in the cholinergic receptor, nicotinic, gamma (CHRNG) gene that encodes for γ-subunit are associated with lethal forms of multiple pterygium and Escobar syndromes (7-9).AChRs have two transmitter binding sites located in the extracellular domain at α-δ and α-γ/e-subunit interfaces. In adult AChRs, the α−δ and α−e sites are equal and independent insofar as each has the same affinity for ACh and supplies the same amount of binding energy for gating (10). In fetal AChRs, the two binding sites are asymmetric with regard to agonist affinity, with estimates for the ratio of resting equilibrium dissociation constants for ACh ranging from ∼5-(11, 12) to >100-fold (13, 14). γ-AChRs also have a longer open channel lifetime, a smaller unitary conductance, and a lower Ca 2+ permeability than e-AChRs (15-17).Fetal AChRs hold a special place in the history of ion channel biophysics. The first single channel recordings from cells were of γ-AChRs (18). They were also the first ion channels to be analyzed according to a thermodynamic cycle, which required quantifying constitutive activity in the absence of agonists (19). These pioneering studies of single channel currents from mouse myotubes led to the estimate that the unliganded gating equilibrium constant of γ-AChRs is ∼1.6 × 10 −6 . γ-AChRs were also the first channels for which the rate and equilibrium constants for closed channel binding and liganded gating were measured (13,(...

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Postsynaptic Development of the Neuromuscular Junction in Mice Lacking the γ-Subunit of Muscle Nicotinic Acetylcholine Receptor

Cited by 13 publications

References 37 publications

Neuromotor synapses in Escobar syndrome

Neuromotor synapses in Escobar syndrome

CHRNG‐related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical, histopathological, and molecular genetic findings

Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response

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