Modulation of acetylcholine receptor function in TE671 (rhabdomyosarcoma) cells by non-AChR ligands: possible relevance to seronegative myasthenia gravis.
The acetylcholine receptor (AChR) is the main target antigen in myasthenia gravis (MG), but about 15% of patients with typical immunologically mediated MG do not have detectable anti-AChR antibodies. Previous studies showed that plasma from these 'seronegative' patients (SNMG) reduced AChR function in the human AChR-expressing TE671 cell line, and it was proposed that SNMG plasmas may act indirectly via phosphorylation of AChR. We show here that substances such as the beta 2-adrenergic agonist, salbutamol, calcitonin-gene-related-peptide (CGRP), and cholera toxin, that increase intracellular cAMP via binding to specific cell-surface receptors, reduced AChR function in TE671 cells. Moreover, non-specific activation of cell surface proteins by lectins achieved similar results. These observations lead us to hypothesise that SNMG immunoglobulins act in TE671 cells by cross-linking of specific cell surface antigen(s) resulting in generation of intracellular cAMP and/or other second messengers. The role of such antibodies at the neuromuscular junction in vivo could be reduction in AChR function by desensitization and/or damage to the postsynaptic membrane following complement activation.
Li
Z
Z
Neurosciences Group, Institute of Molecular Medicine, University of Oxford, UK.
Forester
N
N
Vincent
A
A
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000937:Antigen-Antibody Reactions / Q000187:drug effects; D002038:Bungarotoxins / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D037102:Lectins / Q000494:pharmacology*; D009157:Myasthenia Gravis / Q000276:immunology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000502:physiology*; D012208:Rhabdomyosarcoma / Q000378:metabolism* / Q000473:pathology; D012964:Sodium / Q000378:metabolism; D014403:Tubocurarine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D002038:Bungarotoxins; D037102:Lectins; D018733:Nicotinic Antagonists; D011950:Receptors, Cholinergic; D002772:Cholera Toxin; D012964:Sodium; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide; D014403:Tubocurarine