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Volume 272, Number 20, Issue of May 16, 1997 pp. 12989-12993
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Desensitization and Sequestration of Human m2 Muscarinic Acetylcholine Receptors by Autoantibodies from Patients with Chagas' Disease

(Received for publication, December 21, 1996, and in revised form, March 10, 1997)

Claudia Perez Leiros , Leonor Sterin-Borda , Enri S Borda , Juan Carlos Goin and M. Marlene Hosey ^¶

From the  Centro de Estudios Farmacologicos y Botanicos, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires 1414, Argentina and the ^¶ Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611

Chronic Chagas' disease is associated with pathologic changes of the cardiovascular, digestive, and autonomic nervous system, culminating in autonomic denervation and congestive heart failure. Previously, circulating autoantibodies that activate signaling by cardiac muscarinic acetylcholine receptors (mAChRs) have been described. However, it remains unclear whether the chagasic IgGs directly interact with the m2 mAChRs (predominant cardiac subtype), and, if so, whether chronic exposure of the mAChRs to such activating IgGs would result in receptor desensitization. Here we performed studies with purified and reconstituted hm2 mAChRs and demonstrate that IgGs from chagasic serum immunoprecipitated the mAChRs in a manner similar to an anti-m2 mAChR monoclonal antibody tested in parallel. The chagasic antibodies did not directly interact with the ligand binding site, because the binding of radiolabeled antagonist was unchanged by the addition of the chagasic IgG. In intact cells stably expressing the hm2 mAChR, the chagasic IgGs, but not normal IgGs, mimicked the ability of the agonist acetylcholine to induce two effects associated with agonist-induced receptor desensitization: a decrease in affinity for agonist binding to m2 mAChR and sequestration of the hm2 mAChRs from the cell surface. The results demonstrate that the chagasic IgGs can directly interact with and desensitize m2 mAChRs and provide support for the hypothesis of autoimmune mechanisms having a role in the pathogenesis of Chagas' cardioneuromyopathy.

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