Impairment of agonist-induced M2 muscarinic receptor activation by autoantibodies from chagasic patients with cardiovascular dysautonomia

AUGER, S.R.; WALDNER, C.I.; PAEZ CARRERA; BILDER C; BELTRAME, S.P.; SABRA, A.H.; GOIN, J.C.; AUGER, S.R.; WALDNER, C.I.; PAEZ CARRERA; BILDER C; BELTRAME, S.P.; SABRA, A.H.; GOIN, J.C.

CLINICAL IMMUNOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2020 vol. 212

1521-6616

Previous studies showed that circulating autoantibodies against M2 muscarinic receptors (anti-M2R Ab) areassociated with decreased cardiac parasympathetic modulation in patients with chronic Chagas disease (CD).Here we investigated whether the exposure of M2R to such antibodies could impair agonist-induced receptoractivation, leading to the inhibition of associated signaling pathways. Preincubation of M2R-expressing HEK293T cells with serum IgG fractions from chagasic patients with cardiovascular dysautonomia, followed by theaddition of carbachol, resulted in the attenuation of agonist-induced Gi protein activation and arrestin-2 recruitment. These effects were not mimicked by the corresponding Fab fractions, suggesting that they occurthrough receptor crosslinking. IgG autoantibodies did not enhance M2R/arrestin interaction or promote M2Rinternalization, suggesting that their inhibitory effects are not likely a result of short-term receptor regulation.Rather, these immunoglobulins could function as negative allosteric modulators of acetylcholine-mediated responses, thereby contributing to the development of parasympathetic dysfunction in patients with CD.