Impairment of agonist-induced M2 muscarinic receptor activation by autoantibodies from chagasic patients with cardiovascular dysautonomia
Impairment of agonist-induced M2 muscarinic receptor activation by autoantibodies from chagasic patients with cardiovascular dysautonomia
复制标题
DOI：
10.1016/j.clim.2020.108346
复制
发表时间：
2020-03-01
影响因子：
8.6
通讯作者：
Goin, Juan C.
中科院分区：
文献类型：
--
作者：
Beltrame, Sabrina P.;Carrera Paez, Laura C.;Goin, Juan C.
先前的研究表明，循环中的抗M-2毒蕈碱受体的自身抗体（抗M2 R Ab）与慢性恰加斯病（CD）患者的心脏副交感神经调节降低有关。在这里，我们研究了M2 R暴露于这样的抗体是否会损害激动剂诱导的受体活化，导致相关信号通路的抑制。将表达M2 R的HEK 293 T细胞与来自心血管自主神经功能障碍的chagglutinin患者的血清IgG组分预孵育，然后加入卡巴胆碱，导致激动剂诱导的G（i）蛋白活化和arrestin-2募集减弱。这些作用没有被相应的Fab片段模仿，表明它们通过受体交联发生。IgG自身抗体不增强M2 R/抑制蛋白相互作用或促进M2 R内化，表明其抑制作用不太可能是短期受体调节的结果。相反，这些免疫球蛋白可以作为乙酰胆碱介导的反应的负变构调节剂，从而促进CD患者副交感神经功能障碍的发展。
Previous studies showed that circulating autoantibodies against M-2 muscarinic receptors (anti-M2R Ab) are associated 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 receptor activation, leading to the inhibition of associated signaling pathways. Preincubation of M2R-expressing HEK 293T cells with serum IgG fractions from chagasic patients with cardiovascular dysautonomia, followed by the addition of carbachol, resulted in the attenuation of agonist-induced G(i) protein activation and arrestin-2 recruitment. These effects were not mimicked by the corresponding Fab fractions, suggesting that they occur through receptor crosslinking. IgG autoantibodies did not enhance M2R/arrestin interaction or promote M2R internalization, 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.