Impact of human autoantibodies on β1-adrenergic receptor conformation, activity, and internalization
| Autor: | Lars R. Herda, Stephanie Schmitmeier, Christoph Schäfer, Stephan B. Felix, Jürgen Hescheler, Filomain Nguemo, Beatrice Bornholz, Horst Lemoine, Claus A. M. Seidel, Morten O. Christensen, Fritz Boege, Stefanie Weidtkamp-Peters, Christian Mielke |
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| Rok vydání: | 2012 |
| Předmět: |
Cardiomyopathy
Dilated Chronotropic medicine.medical_specialty Human embryonic cardiomyocytes Protein Conformation Physiology media_common.quotation_subject Dilated cardiomyopathy Pilot Projects Stimulation Receptor conformation Immunoglobulin G Physiology (medical) Internal medicine Cyclic AMP medicine Humans Myocytes Cardiac Receptor Internalization Cells Cultured Autoantibodies media_common Cardiac Biology and Remodelling biology Chemistry Isoproterenol Autoantibody Colocalization Original Articles Adrenergic beta-Agonists β1-Adrenergic receptors HEK293 Cells Endocrinology IgG binding Case-Control Studies biology.protein Receptors Adrenergic beta-1 Cardiology and Cardiovascular Medicine |
| Zdroj: | Cardiovascular Research |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvs350 |
| Popis: | Aims Autoantibodies against second extracellular loops of β1-adrenergic receptors frequent in dilated cardiomyopathy confer myocardial dysfunction presumably via cAMP stimulation. Here, we investigate the autoantibody impact on receptor conformation and function. Methods and results IgG was prepared from patients with dilated cardiomyopathy, matched healthy donors (10 each) or commercial IgG preparations (2). IgG binding to β1-adrenergic receptor peptides was detected in 5 of 10 patients and 2 of 10 controls. IgG colocalization with the native receptor was detected in 8 of 10 patients and 1 of 10 controls (10 of 10 patients and 7 of 10 controls at >30 mg IgG/L). All IgGs exhibiting receptor colocalization triggered changes in receptor conformation (determined with fluorescent sensors) not stringently correlated to cAMP stimulation, suggesting the induction of more or less active receptor conformations. Receptor-activating IgG was detected in 8 of 10 patients but only 1 of 10 controls. In addition, IgG from 8 of 10 patients and 3 of 10 controls attenuated receptor internalization (measured by total internal reflection fluorescence microscopy). IgG-inducing inactive receptor conformations had no effect on subsequent cAMP stimulation by isoproterenol. IgG-inducing active receptor conformations dampened or augmented subsequent cAMP stimulation by isoproterenol, depending on whether receptor internalization was attenuated or not. Corresponding IgG effects on the basal beating rate and chronotropic isoproterenol response of embryonic human cardiomyocytes were observed. Conclusions (i) Autoantibodies trigger conformation changes in the β1-adrenergic receptor molecule. (ii) Some also attenuate receptor internalization. (iii) Combinations thereof increase the basal beating rate of cardiomyocytes and optionally entail dampening of their chronotropic catecholamine responses. (iv) The latter effects seem specific for patient autoantibodies, which also have higher levels. |
| Databáze: | OpenAIRE |
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