Structure of the acetylcholine receptor and specificities of antibodies to it in myasthenia gravis.

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Acetylcholine receptors in skeletal muscle and fish electric organs are intrinsic membrane proteins whose function is to bind acetylcholine released from the nerve ending and trigger the opening of a cation-specific channel in the postsynaptic membrane, thereby facilitating transmission of the nerve signal to the muscle. Investigations from several laboratories indicate that acetylcholine receptors from fish electric organs are composed of four homologous glycoprotein subunits of apparent relative molecular masses (Mr) approximating 40, 50, 57 and 64 x 10(3) designated, respectively, alpha, beta, gamma and delta. These subunits are present in receptor monomers in the mole ratio alpha 2 beta gamma delta. Receptor purified from skeletal muscle appears to have a similar structure. The alpha subunits are unknown. It is known that the cation channel regulated by acetylcholine binding is located within the receptor monomer. Experimental autoimmune myasthenia gravis (EAMG) is induced by immunizing animals with purified receptor. The mechanisms by which neuromuscular transmission is impaired in this model are very similar to those in myasthenia gravis (MG). Although there are many immunogenic determinants on receptors, and EAMG can be induced in rats by any of the denatured subunits, there is a main immunogenic region at which most of the antibodies to native receptors are directed. The main immunogenic region is a conformationally dependent part of the external surface of alpha subunits other than the acetylcholine-binding site or the attached carbohydrate. Antisera from MG patients are also directed primarily at this region. No correlation was detected between the specificities of antibodies to receptor in patients' sera and the severity of their weakness.