Abstract
Antibody against acetylcholine receptor induces an increase in the rate of degradation of acetylcholine receptors on a mouse cell line (BC3H-1) and cultured rat skeletal muscle. The increased rate of degradation results in a lowered density of acetylcholine receptors on muscle membrane and a lowered sensitivity to iontophoretically applied acetylcholine. The modulation of acetylcholine receptor is energy, temperature, and time dependent and may be related to antigenic modulation found in other systems. Acetylcholine noise analysis demonstrates that antibody against acetylcholine receptor reduces the channel mean conductance and mean open time slightly.
It is concluded that antibody binds to the acetylcholine receptor, impairs its function, and induces receptor degradation. This results in a lowered density of acetylcholine receptor and a lowered sensitivity to acetylcholine. Patients with myasthenia gravis have antibodies to their acetylcholine receptor in their serum. Antigenic modulation of receptor in the muscle of patients with myasthenia gravis could contribute to the observed decrease in amplitudes of miniature endplate potentials and in muscle acetylcholine sensitivity, and the symptoms of muscular weakness.
Keywords: muscle, acetylcholine sensitivity, acetylcholine noise, myasthenia gravis
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aharonov A., Abramsky O., Tarrab-Hazdai R., Fuchs S. Humoral antibodies to acetylcholine receptor in patients with myasthenia gravis. Lancet. 1975 Aug 23;2(7930):340–342. doi: 10.1016/s0140-6736(75)92779-8. [DOI] [PubMed] [Google Scholar]
- Albuquerque E. X., Lebeda F. J., Appel S. H., Almon R., Kauffman F. C., Mayer R. F., Narahashi T., Yeh J. Z. Effects of normal and myasthenic serum factors on innervated and chronically denervated mammalian muscles. Ann N Y Acad Sci. 1976;274:475–492. doi: 10.1111/j.1749-6632.1976.tb47709.x. [DOI] [PubMed] [Google Scholar]
- Albuquerque E. X., Rash J. E., Mayer R. F., Satterfield J. R. An electrophysiological and morphological study of the neuromuscular junction in patients with myasthenia gravis. Exp Neurol. 1976 Jun;51(3):536–563. doi: 10.1016/0014-4886(76)90179-5. [DOI] [PubMed] [Google Scholar]
- Almon R. R., Andrew C. G., Appel S. H. Serum globulin in myasthenia gravis: inhibition of alpha-bungarotoxin binding to acetylcholine receptors. Science. 1974 Oct 4;186(4158):55–57. doi: 10.1126/science.186.4158.55. [DOI] [PubMed] [Google Scholar]
- Anderson C. R., Stevens C. F. Voltage clamp analysis of acetylcholine produced end-plate current fluctuations at frog neuromuscular junction. J Physiol. 1973 Dec;235(3):655–691. doi: 10.1113/jphysiol.1973.sp010410. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bender A. N., Ringel S. P., Engel W. K., Daniels M. P., Vogel Z. Myasthenia gravis: a serum factor blocking acetylcholine receptors of the human neuromuscular junction. Lancet. 1975 Mar 15;1(7907):607–609. doi: 10.1016/s0140-6736(75)91886-3. [DOI] [PubMed] [Google Scholar]
- Berg D. K., Hall Z. W. Loss of alpha-bungarotoxin from junctional and extrajunctional acetylcholine receptors in rat diaphragm muscle in vivo and in organ culture. J Physiol. 1975 Nov;252(3):771–789. doi: 10.1113/jphysiol.1975.sp011169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Beránek R., Vyskocil F. The action of tubocurarine and atropine on the normal and denervated rat diaphragm. J Physiol. 1967 Jan;188(1):53–66. doi: 10.1113/jphysiol.1967.sp008123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bevan S., Heinemann S., Lennon V. A., Lindstrom J. Reduced muscle acetylcholine sensitivity in rats immunised with acetylcholine receptor. Nature. 1976 Apr 1;260(5550):438–439. doi: 10.1038/260438a0. [DOI] [PubMed] [Google Scholar]
- Brockes J. P., Hall Z. W. Acetylcholine receptors in normal and denervated rat diaphragm muscle. II. Comparison of junctional and extrajunctional receptors. Biochemistry. 1975 May 20;14(10):2100–2106. doi: 10.1021/bi00681a009. [DOI] [PubMed] [Google Scholar]
- Chang C. C., Huang M. C. Turnover of junctional and extrajunctional acetylcholine receptors of the rat diaphragm. Nature. 1975 Feb 20;253(5493):643–644. doi: 10.1038/253643a0. [DOI] [PubMed] [Google Scholar]
- Devreotes P. N., Fambrough D. M. Acetylcholine receptor turnover in membranes of developing muscle fibers. J Cell Biol. 1975 May;65(2):335–358. doi: 10.1083/jcb.65.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Devreotes P. N., Gardner J. M., Fambrough D. M. Kinetics of biosynthesis of acetylcholine receptor and subsequent incorporation into plasma membrane of cultured chick skeletal muscle. Cell. 1977 Mar;10(3):365–373. doi: 10.1016/0092-8674(77)90023-x. [DOI] [PubMed] [Google Scholar]
- ELMQVIST D., HOFMANN W. W., KUGELBERG J., QUASTEL D. M. AN ELECTROPHYSIOLOGICAL INVESTIGATION OF NEUROMUSCULAR TRANSMISSION IN MYASTHENIA GRAVIS. J Physiol. 1964 Nov;174:417–434. doi: 10.1113/jphysiol.1964.sp007495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fambrough D. M., Drachman D. B., Satyamurti S. Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science. 1973 Oct 19;182(4109):293–295. doi: 10.1126/science.182.4109.293. [DOI] [PubMed] [Google Scholar]
- Gavin J. R., 3rd, Roth J., Neville D. M., Jr, de Meyts P., Buell D. N. Insulin-dependent regulation of insulin receptor concentrations: a direct demonstration in cell culture. Proc Natl Acad Sci U S A. 1974 Jan;71(1):84–88. doi: 10.1073/pnas.71.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hinkle P. M., Tashjian A. H., Jr Thyrotropin-releasing hormone regulates the number of its own receptors in the GH3 strain of pituitary cells in culture. Biochemistry. 1975 Aug 26;14(17):3845–3851. doi: 10.1021/bi00688a017. [DOI] [PubMed] [Google Scholar]
- KATZ B., MILEDI R. THE DEVELOPMENT OF ACETYLCHOLINE SENSITIVITY IN NERVE-FREE SEGMENTS OF SKELETAL MUSCLE. J Physiol. 1964 Mar;170:389–396. doi: 10.1113/jphysiol.1964.sp007339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Katz B., Miledi R. The statistical nature of the acetycholine potential and its molecular components. J Physiol. 1972 Aug;224(3):665–699. doi: 10.1113/jphysiol.1972.sp009918. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kebabian J. W., Zatz M., Romero J. A., Axelrod J. Rapid changes in rat pineal beta-adrenergic receptor: alterations in l-(3H)alprenolol binding and adenylate cyclase. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3735–3739. doi: 10.1073/pnas.72.9.3735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lambert E. H., Lindstrom J. M., Lennon V. A. End-plate potentials in experimental autoimmune myasthenia gravis in rats. Ann N Y Acad Sci. 1976;274:300–318. doi: 10.1111/j.1749-6632.1976.tb47694.x. [DOI] [PubMed] [Google Scholar]
- Lamm M. E., Boyse E. A., Old L. J., Lisowska-Bernstein B., Stockert E. Modulation of TL (thymus-leukemia) antigens by Fab-fragments of TL antibody. J Immunol. 1968 Jul;101(1):99–103. [PubMed] [Google Scholar]
- Lee C. Y., Tseng L. F., Chiu T. H. Influence of denervation on localization of neurotoxins from clapid venoms in rat diaphragm. Nature. 1967 Sep 9;215(5106):1177–1178. doi: 10.1038/2151177a0. [DOI] [PubMed] [Google Scholar]
- Lesley J., Hyman R. Antibody-induced changes in expression of the H-2 antigen. Eur J Immunol. 1974 Nov;4(11):732–739. doi: 10.1002/eji.1830041106. [DOI] [PubMed] [Google Scholar]
- Lindstrom J. M., Einarson B. L., Lennon V. A., Seybold M. E. Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis. J Exp Med. 1976 Sep 1;144(3):726–738. doi: 10.1084/jem.144.3.726. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lindstrom J. M., Lennon V. A., Seybold M. E., Whittingham S. Experimental autoimmune myasthenia gravis and myasthenia gravis: biochemical and immunochemical aspects. Ann N Y Acad Sci. 1976;274:254–274. doi: 10.1111/j.1749-6632.1976.tb47691.x. [DOI] [PubMed] [Google Scholar]
- Lindstrom J. M., Seybold M. E., Lennon V. A., Whittingham S., Duane D. D. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology. 1976 Nov;26(11):1054–1059. doi: 10.1212/wnl.26.11.1054. [DOI] [PubMed] [Google Scholar]
- Merlie J. P., Changeux J. P., Gros F. Acetylcholine receptor degradation measured by pulse chase labelling. Nature. 1976 Nov 4;264(5581):74–76. doi: 10.1038/264074a0. [DOI] [PubMed] [Google Scholar]
- Mukherjee C., Caron M. G., Lefkowitz R. J. Catecholamine-induced subsensitivity of adenylate cyclase associated with loss of beta-adrenergic receptor binding sites. Proc Natl Acad Sci U S A. 1975 May;72(5):1945–1949. doi: 10.1073/pnas.72.5.1945. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Neher E., Sakmann B. Voltage-dependence of drug-induced conductance in frog neuromuscular junction. Proc Natl Acad Sci U S A. 1975 Jun;72(6):2140–2144. doi: 10.1073/pnas.72.6.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Patrick J., Heinemann S. F., Lindstrom J., Schubert D., Steinbach J. H. Appearance of acetylcholine receptors during differentiation of a myogenic cell line. Proc Natl Acad Sci U S A. 1972 Oct;69(10):2762–2766. doi: 10.1073/pnas.69.10.2762. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Patrick J., McMillan J., Wolfson H., O'Brien J. C. Acetylcholine receptor metabolism in a nonfusing muscle cell line. J Biol Chem. 1977 Mar 25;252(6):2143–2153. [PubMed] [Google Scholar]
- Schubert D., Harris A. J., Devine C. E., Heinemann S. Characterization of a unique muscle cell line. J Cell Biol. 1974 May;61(2):398–413. doi: 10.1083/jcb.61.2.398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Steinbach J. H., Harris A. J., Patrick J., Schubert D., Heinemann S. Nerve-muscle interaction in vitro. Role of acetylcholine. J Gen Physiol. 1973 Sep;62(3):255–270. doi: 10.1085/jgp.62.3.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vogel Z., Sytkowski A. J., Nirenberg M. W. Acetylcholine receptors of muscle grown in vitro. Proc Natl Acad Sci U S A. 1972 Nov;69(11):3180–3184. doi: 10.1073/pnas.69.11.3180. [DOI] [PMC free article] [PubMed] [Google Scholar]