SEARCH · PubMed Health

Results for “acetylcholine receptor (AChR)”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2026

Clinical Variability and Genotype-Driven Outcomes in CHRND-Related Congenital Myasthenic Syndrome.

BACKGROUND: Congenital myasthenic syndromes (CMS) caused by pathogenic variants in CHRND, encoding the δ-subunit of the nicotinic acetylcholine receptor (AChR), are rare, and data on genotype-phenotype correlations and long-term outcomes are limited. METHODS: We performed a retrospective, multicenter study of nine patients with genetically confirmed CHRND-related CMS from specialized neuromuscular centers. Clinical, electrophysiological, genetic, and therapeutic data were systematically collected. All diagnoses were established by exome sequencing during routine clinical work-up. RESULTS: Eight patients were compound heterozygous and one was homozygous for pathogenic CHRND variants, including nonsense, missense, splice-site variants, and one microdeletion. Disease onset ranged from the neonatal period (n = 7) to adolescence (n = 2). Three patients were followed longitudinally for 22-43 years. Ocular involvement, particularly ptosis and ophthalmoparesis, was present in all patients. Generalized fatigable weakness was common, whereas bulbar and respiratory involvement occurred in a subset and reflected overall disease severity. Genotypes including a null allele or a homozygous missense variant tended to be associated with more severe phenotypes, while compound heterozygous missense variants were linked to a broader and generally milder spectrum, sometimes limited to ocular symptoms. Long-term outcomes ranged from minimal symptoms under therapy to severe motor impairment with respiratory insufficiency, highlighting substantial interindividual variability. CONCLUSIONS: This study expands the phenotypic and genotypic spectrum of CHRND-related CMS and underscores the critical role of genotype in determining disease severity. Comprehensive genetic testing, longitudinal phenotyping, and genotype-informed management are essential for optimal diagnosis and care in this rare disorder.

Humans↗

PubMedDate not supplied

Antigenic modulation and receptor loss in experimental autoimmune myasthenia gravis.

Immunization of groups of rats with 0.1- 100 microgram of acetylcholine receptor (AChR) purified from the electric organ of Torpedo californica resulted in dose-dependent (1) loss of acetylcholine receptor from the rats' muscles, (2) binding of antibodies to many of the receptors remaining in muscle and (3) production of antibodies in serum capable of cross-reacting with receptor solubilized from rat muscle. Addition of antibodies from rats immunized with electric organ acetylcholine receptors to muscle cells in culture caused loss of receptor by accelerating the rate of receptor degradation. Monovalent antibody fragments did not accelerate degradation unless antiantibody was added to cross-link the monovalent antibody fragments bound to receptors. This indicates that cross-linking of receptors by antibody molecules triggers accelerated receptor degradation, leading to receptor loss. The rate of increase in receptor destruction due to antigenic modulation observed in vitro appears sufficient to account for the extent of receptor loss observed in vivo. Endocytosis of antibody cross-linked receptors may be a rate-limiting step common to antigenic modulation in vitro and in vivo.

Antigen-Antibody Reactions↗

PubMed2026

Pathogenic properties of myasthenia gravis AChR autoantibodies associate with clinical response to efgartigimod.

BACKGROUND: Efgartigimod, a neonatal Fc receptor (FcRn) blocker, effectively reduces total IgG, including pathogenic acetylcholine receptor (AChR) autoantibodies in myasthenia gravis (MG); however, clinical responses vary. To investigate this variability, we studied how efgartigimod impacts AChR-specific autoantibody profiles and associated pathogenic mechanisms, including complement activation, AChR internalisation and ACh-binding site blockade. METHODS: Serum samples (N=150) were sourced from 50 AChR autoantibody-positive generalised MG patients participating in the phase 3 ADAPT study, randomised to receive efgartigimod (N=40) or placebo (N=10) in cycles of 4-weekly infusions. Samples were collected at baseline, day 29 and day 57 during the first cycle. Live cell-based assays quantified AChR-specific IgG subclasses and isotypes and assessed their capacity to mediate pathomechanisms. RESULTS: Efgartigimod decreased all detectable AChR-specific IgG subclasses. At baseline, AChR autoantibody-mediated C3b deposition, AChR internalisation and ACh-binding site blockade were detected in 42 (84%), 41 (82%) and 10 (20%) patients, respectively. After 4-weekly infusions of efgartigimod, the magnitude of all three pathomechanisms was significantly decreased. However, the extent of this reduction varied across individuals. Double responders on both MG-activities of daily living and quantitative MG scores demonstrated a greater reduction in complement activity and AChR internalisation compared with patients who responded on only one score or were double non-responders. In addition, efgartigimod reduced IgG-dependent IgM binding to AChR. CONCLUSIONS: These findings suggest that clinical efficacy may be more closely associated with functional modulation of the AChR-specific autoantibodies than with their absolute quantity alone. These results support the evaluation of mechanistic pathway monitoring as a potential strategy to predict or guide efgartigimod treatment response.

Humans↗

PubMed2022

Heterogeneity of Acetylcholine Receptor Autoantibody-Mediated Complement Activity in Patients With Myasthenia Gravis.

BACKGROUND AND OBJECTIVES: Autoantibodies targeting the acetylcholine receptor (AChR), found in patients with myasthenia gravis (MG), mediate pathology through 3 mechanisms: complement-directed tissue damage, blocking of the acetylcholine binding site, and internalization of the AChR. Clinical assays, used to diagnose and monitor patients, measure only autoantibody binding. Consequently, they are limited in providing association with disease burden, understanding of mechanistic heterogeneity, and monitoring therapeutic response. The objective of this study was to develop a cell-based assay that measures AChR autoantibody-mediated complement membrane attack complex (MAC) formation. METHODS: An HEK293T cell line-modified using CRISPR/Cas9 genome editing to disrupt expression of the complement regulator genes (CD46, CD55, and CD59)-was used to measure AChR autoantibody-mediated MAC formation through flow cytometry. RESULTS: Serum samples (n = 155) from 96 clinically confirmed AChR MG patients, representing a wide range of disease burden and autoantibody titer, were tested along with 32 healthy donor (HD) samples. AChR autoantibodies were detected in 139 of the 155 (89.7%) MG samples through a cell-based assay. Of the 139 AChR-positive samples, autoantibody-mediated MAC formation was detected in 83 (59.7%), whereas MAC formation was undetectable in the HD group or AChR-positive samples with low autoantibody levels. MAC formation was positively associated with autoantibody binding in most patient samples; ratios (mean fluorescence intensity) of MAC formation to AChR autoantibody binding ranged between 0.27 and 48, with a median of 0.79 and an interquartile range of 0.43 (0.58-1.1). However, the distribution of ratios was asymmetric and included extreme values; 16 samples were beyond the 10-90 percentile, with high MAC to low AChR autoantibody binding ratio or the reverse. Correlation between MAC formation and clinical disease scores suggested a modest positive association (rho = 0.34, p = 0.0023), which included a subset of outliers that did not follow this pattern. MAC formation did not associate with exposure to immunotherapy, thymectomy, or MG subtypes defined by age-of-onset. DISCUSSION: A novel assay for evaluating AChR autoantibody-mediated complement activity was developed. A subset of patients that lacks association between MAC formation and autoantibody binding or disease burden was identified. The assay may provide a better understanding of the heterogeneous autoantibody molecular pathology and identify patients expected to benefit from complement inhibitor therapy.

Autoantibodies↗

PubMed1979

Localization of acetylcholine receptors by means of horseradish peroxidase-alpha-bungarotoxin during formation and development of the neuromuscular junction in the chick embryo.

The localization of acetylcholine receptors (AChR) in the surface of developing myogenic cells of the chick embryo anterior and posterior latissimus dorsi muscles in relation to the process of innervation has been studied at the ultrastructural level utilizing a horseradish peroxidase-alpha-bungarotoxin conjugate. Localized concentrations of AChR were found in small regions 0.1-0.4 micron in width on the surface of myogenic cells of 10- to 14-d-old muscles. Surface specializations consisting of an external coating of extraneous material and an internal accumulation of dense material are associated with the plasma membrane in the regions of AChR concentration. As the muscle fibers are innervated, reactive surface patches are found at the region of contact of the growing nerve fiber and the surface of myotubes or their fusing myoblasts. After the establishment of contact, the patches of reaction product become more numerous and coextensive within the region of the neuromuscular junction and its immediate surroundings forming a dense continuous deposit on the postsynaptic sarcolemma. Activity becomes increasingly restricted to the site of the neuromuscular junction as the embryos approach hatching. At all stages, specializations external and internal to the plasmalemma are found at regions of high density of AChR, suggesting that they play a role in the maintenance of a higher concentration of receptors at these sites. These specializations also occur at the region of initial synaptic contact, indicating that they might be recognized by the nerve and represent preferred sites of innervation. Innervation appears to exert a stabilizing influence on the area of high AChR concentration in contact with the nerve and to induce a further increase in the AChR density of this site while the number of AChR in the remaining portions of the muscle surface declines.

Acetylcholine↗

PubMed1975

Humoral antibodies to acetylcholine receptor in patients with myasthenia gravis.

Sera from patients with myasthenia gravis (M.G.) were studied by the quantitative micro-scale complement-fixation assay for the presence of humoral antibodies against acetylcholine receptor (AChR). The purified receptor was extracted from the electrogenic tissue of the electric ray, Torpedo californica. A significant difference in the antibody titres was observed between myasthenic and non-myasthenic patients. Out of fifteen patients with myasthenia gravis, at least 12 (80%) had antibodies against AChR. Only one case out of twenty-four controls had an indication of anti-receptor antibodies. In view of observations on the role of AChR as the autoantigen in myasthenia gravis, such antibodies may have significance in producing the neuro-muscular block characteristic of the disease.

Acetylcholine↗

PubMed1978

Histochemistry and acetylcholine receptor distribution in normal and denervated monkey extraocular muscles.

In monkey extraocular muscles (EOM), a battery of histochemical reactions delineates three muscle fiber types, coarse, fine, and granular. Normal EOM are compared with EOM denervated by intracranial oculomotor nerve section. The experimentally denervated EOM fibers did not show the constellation of histologic responses typical of denervated limb muscle, making a diagnosis of a denervation process in EOM muscle very difficult. Although the denervated fine and granular fibers (but not the coarse fibers) develop diffuse extrajunctional acetylcholine receptors (AChR) following experimental denervation, this is not a reliable criterion of denervation because not all of those fibers developed it and they did not show it beyond a 12-week period following nerve section; moreover, myopathic mechanisms have previously been shown capable of provoking diffuse extrajunctional AChR in limb-muscle fibers.

Acetylcholine↗

PubMed1977

Morphologic and immunologic studies in experimental autoimmune myasthenia gravis and myasthenia gravis.

An indirect immunoperoxidase technique was used to study by light microscopy the binding of serum from experimental autoimmune myasthenia gravis (EAMG) rabbits to junctionally and extrajunctionally located acetylcholine receptors (AChRs) in human and rat muscles. Binding was restricted to junctional AChR. Alpha bungarotoxin (a-BGT) partially blocked the binding of EAMG serum, while myasthenia gravis serum, carbamylcholine, decamethonium, and tubocurarine did not. A radioimmunoassay showed significant binding of antibodies in EAMG sera to 125l AChR. This binding was not inhibited by a-BGT, nor by carbamylcholine, decamethonium, or tubocurarine. Sera from 10 myasthenia gravis patients did not contain antibodies binding to the 125l AChR. We suggest that EAMG in rabbits induced by Torpedo AChR differs serologically from myasthenia gravis in patients, probably owing to antigenic differences between Torpedo and human AChR, and that antigenic differences also exist between junctional and extrajunctional receptors.

Acetylcholine↗

PubMedDate not supplied

[Study of the molecular structure and mechanisms of pond snail neuron cholinoreceptor function by means of in vivo chemical modification].

The molecular structure of acetylcholine receptors (AChR) of Lymnaea stagnalis neurons has been studied using specific agents to definite chemical groups. The disulphide bond important for AChR function was discovered, the reduction of which by dithiotreitol (DTT) inactivates AChR. The drugs exciting AChR protect the disulphide bond against modification with DTT likely due to the conformational changes of an active site and its environment. Desensitized AChR can also be modified by DDT (if it is not occupied by agonist). It is suggested that the system transmitting the conformational change from the AChR active site to its ionophore is responsible for desensitization.

Acetylcholine↗

PubMed1977

Duchenne dystrophy: ultrastructural localization of the acetylcholine receptor and intracellular microelectrode studies of neuromuscular transmission.

Despite focal degeneration and simplification of the postsynaptic region in Duchenne dystrophy, the postsynaptic acetylcholine receptor (AChR) is preserved. This is in contrast to myasthenia gravis where similar postsynaptic alterations are invariably associated with a marked decrease in AChR. There is no extrajunctional spread of AChR in Duchenne dystrophy. The amplitude and frequency of miniature end-plate potentials and the number of transmitter quanta released by nerve impulse are normal but the resting membrane potential is lower than normal. The findings indicate that the release and the postsynaptic responsiveness to acetylcholine are intact in Duchenne dystrophy.

Acetylcholine↗

PubMed1978

Association of HLA-B8, DRw3, and anti-acetylcholine receptor antibodies in myasthenia gravis.

Twenty-eight patients with myasthenia gravis (MG), five with and 23 without thymoma, and 47 normal controls were typed for serologically defined HLA-A, B, C, and DRw antigens. Sera from all patients were titered for antibodies to acetylcholine receptors (AChR). The frequency of HLA-B8 and DRw3 in the non-thymoma MG patients was significantly higher than in the normal population. Most of the non-thymoma patients with AChR titers higher than the average level were positive for HLA-B8 and/or DRw3, while the majority of the HLA-B8(-) and/or DRw3(-) non-thymoma patients demonstrated AChR titers below average. These findings support the possibility of the existence of immune response genes in the HLA-B, DRw segment of the major histocompatibility complex which are concerned in the response to or recognition of autoantigens.

Acetylcholine↗

PubMed1976

Differential effects of mercurial compounds on excitable tissues.

Sarcoplasmic reticulum (SR), Ca2+ plus Mg2+-ATPase, and Ca2+-ionophore were obtained from white rabbit skeletal muscles. Methylmercury inhibited the Ca2+ plus Mg2+-ATPase and Ca2+-transport but had no effect on the Ca2+-ionophore. Mercuric chloride inhibited all three functions (i.e., ATPase, transport and ionophoric activity). The mechanism of HgCl2 inhibition of the Ca2+-ionophore was by competition with Ca2+ for Ca2+-ionophoric site whereas its inhibition of the enzyme and Ca2+-transport was due to the blockage of essential sulfhydryl (--SH) groups. Ca2+ plus Mg2+-ATPase and Ca2+-transport were more sensitive to methylmercury than to HgCl2. Acetylcholine receptor (AChR) was obtained for the electric organ of T. californica. Methylmercury inhibited the ACh binding to AChR WITH Ki = 5.7 - 10(-6) M. This effect was not due to mercuric ion alone since mercuric chloride up to 10(-4) M did not affect ACh binding to AChR. It is concluded that: the Ca2+ plus Mg2+-ATPase and Ca2+-transport contain --SH groups essential for their activity, and that the two functions are tightly coupled; the Ca2+-ionophore contains no --SH groups essential for its activity; CH3HgCl inhibition of Ca2+ plus Mg2+-ATPase and Ca2+-transport is partly due to its reactivity with --SH groups in hydrophobic environment; the Ca2+-transport is inhibited by HgCl2 through two processes, one which is the blockage of --SH groups and another which is the inhibition of the Ca2+-ionophoric site; and the inhibition of ACh binding to AChR is due to the blockage of --SH groups in hydrophobic environment, which is inaccessible to Hg2+. Our data present for the first time a molecular basis for the myopathy associated with mercurial compounds toxicity.

Acetylcholine↗

PubMed1979

Dispersal and reformation of acetylcholine receptor clusters of cultured rat myotubes treated with inhibitors of energy metabolism.

The effects of energy metabolism inhibitors on the distribution of acetylcholine receptors (AChRs) in the surface membranes of non-innervated, cultured rat myotubes were studied by visualizing the AChRs with monotetramethylrhodamine-alpha-bungarotoxin. Incubation of myotubes with inhibitors of energy metabolism causes a large decrease in the fraction of myotubes displaying clusters of AChR. This decrease is reversible, and is dependent on temperature, the concentration of inhibitor, and the duration of treatment. Cluster dispersal is probably not the result of secondary effects on Ca++ or cyclic nucleotide metabolism, membrane potential, cytoskeletal elements, or protein synthesis. Sequential observations of identified cells treated with sodium azide showed that clusters appear to disperse by movements of receptors within the sarcolemma without accompanying changes in cell shape. AChR clusters dispersed by pretreating cells with sodium azide rapidly reform upon removal of the inhibitor. Reclustering involves the formation of small aggregates of AChR, which act as foci for further aggregation and which appear to be precursors of large AChR clusters. Small AChR aggregates also appear to be precursors of clusters which form on myotubes never exposed to azide. Reclustering after azide treatment does not necessarily occur at the same sites occupied by clusters before dispersal, nor does it employ only receptors which had previously been in clusters. Cluster reformation can be blocked by cycloheximide, colchicine, and drugs which alter the intracellular cation composition.

Acetylcholine↗

PubMed1979

Long-term effects of repeated plasma exchange in myasthenia gravis.

Plasma exchange produces a short-term clinical improvement in myasthenia gravis (M.G.) which may be attributable to removal of acetylcholine receptor (AChR) antibody. The possibility that repeated plasma exchanges might confer cumulative long-term benefits was investigated. Serum-AChR-antibody and clinical response were followed for 4--12 months (mean 8 months) in six M.G. patients receiving 4--25 plasma exchanges of 2--4 1 together with immunosuppressive drugs (azathioprine [2.5 mg/kg] with or without alternate-day prednisone therapy), and in seven M.G. patients on immunosuppressive drugs alone. Percentage decrease in AChR antibody was not significantly different in the two treatment groups. Decline in antibody titre was associated with clinical improvement. Eight patients with previous thymoma showed significantly greater decline in antibody than the remaining five patients, irrespective of plasma exchange. Since repeated plasma exchange had no cumulative long-term benefit, the value of this treatment as used here lies only in short-term control of severe M.G. symptoms.

Acetylcholine↗

PubMed1979

Antibodies to motor endplates demonstrated with the immunofluorescence technique.

Antibodies to acetylcholine receptors (AChR) are probably directly responsible for the pathogenesis of myasthenia gravis (MG). Methods for the demonstration of these antibodies are complicated. The present study shows that the antibodies can also be revealed by the use of the simple indirect immunofluorescence technique with rat diaphragm as substrate. Antibodies were demonstrated with FITC-labelled anti-human Ig. The location on the motor endplates was confirmed by using a TRITC-labelled anti-alpha-bungarotoxin system. Antibodies to motor endplates were only demonstrated in MG and not in either twenty-two patients with neuromuscular disorders or fifty normal subjects. Antibodies to motor endplates were found in only twelve out of fifty-seven MG patients. In fifteen of the other forty-five patients, antibodies were found of the classical anti-skeletal muscle type, 'overluminating' the anti-motor endplate antibodies.

Acetylcholine↗

PubMed2026

The miR-206-3p/Cpeb1 axis delays acetylcholine receptor degradation and preserves neuromuscular junction stability in denervation-induced muscle atrophy.

Peripheral nerve injury leads to progressive neuromuscular junction (NMJ) destabilization and acetylcholine receptor (AChR) degradation, which are critical drivers of denervation-induced muscle atrophy and impaired motor recovery. However, the post-transcriptional mechanisms regulating AChR stability during denervation remain poorly understood. Here, we investigated the role of miR-206-3p in NMJ maintenance and muscle preservation after denervation, with a focus on its interaction with the RNA-binding protein cytoplasmic polyadenylation element binding protein 1 (Cpeb1). Using C2C12 myoblasts and a sciatic nerve transection mouse model, we demonstrate that miR-206-3p promotes myogenic differentiation, enhances AChR clustering, and preserves postsynaptic AChR morphology. miR-206-3p directly targets the 3' untranslated region of Cpeb1, suppressing its expression, as confirmed by dual-luciferase reporter assays. In vivo, adeno-associated virus-mediated overexpression of miR-206-3p delayed denervation-induced AChR fragmentation, attenuated muscle atrophy, and significantly improved motor function recovery. Conversely, Cpeb1 overexpression accelerated AChR degradation and muscle wasting, whereas co-overexpression of miR-206-3p mitigated these detrimental effects, indicating that Cpeb1 is a key downstream effector of miR-206-3p. Collectively, our findings identify the miR-206-3p/Cpeb1 axis as a previously unrecognized regulator of NMJ stability and muscle integrity after denervation, providing mechanistic insight and a potential therapeutic target for preserving neuromuscular function during prolonged denervation.

Animals↗

PubMed1979

Phosphorylation of the membrane-bound acetylcholine receptor: inhibition by diphenylhydantoin.

Purified postsynaptic membranes can be used as a model system to study the regulation of synaptic membrane proteins. These membranes contain protein kinase activity that phosphorylates the acetylcholine receptor (AChR). We find that diphenylhydantoin (DPH) interacts with these membranes to inhibit phosphorylation of the membrane-bound AChR. DPH appears to alter the availability of postsynaptic membrane proteins for phosphorylation by a synaptic membrane protein kinase. The concentration of DPH that produces half-maximal inhibition of AChR phosphorylation is about 5 x 10(-5) M. This suggests that one of the specific effects of DPH in the nervous system may be related to inhibition of phosphorylation of postsynaptic membrane proteins.

Animals↗

PubMed1979

Extraocular muscle biopsy in chronic progressive external ophthalmoplegia.

A quantitatives assessment of the pathological changes in extraocular muscle is presented in 8 patients with chronic progressive external ophthalmoplegia (CPEO). Serial cross-sections of extraocular muscle were stained with a battery of histochemical and immunohistochemical techniques and compared with 36 normal extraocular muscles and 1 muscle from a patient who had longstanding third nerve plasy with anomalous reinnervation. Several of the patients had a striking increase in the number of ragged-red fibers in extraocular muscle, particularly if frequent ragged-red fibers also were found on limb muscle biopsy. One patients demonstrated extrajunctional acetylcholine receptor (AChR) in a small percentage of fibers, although this finding was not present in the reinnervated muscle. Numerous darkly staining central regions were noted in the ocular muscle fibers of a patient with Stephens syndrome (CPEO, peripheral neuropathy, and cerebellar disease) and in the reinnervated muscle. A patient with myotubular myopathy had single central nuclei in both limb and ocular muscle. All patients demonstrated in their extraocular muscles variation in both the size and distribution of each of the three histochemical fiber types. Extraocular muscle biopsy proved to be a safe, reliable technique. As a similar quantitative analysis is applied to the study of further patients, a better understanding of the pathogenesis of CPEO should be possible.

Adolescent↗