The IgG3 subclass of β1-adrenergic receptor autoantibodies is an endogenous biaser of β1AR signaling

• DOI: 10.1091/mbc.e20-06-0394
• Publication Date: 2021-02-03T17:24:06Z
• Authors: Maradumane L. Mohan; Yuji Nagatomo; Prasenjit Prasad ...; Sromona D. Mukherjee; Timothy Engelman; Rommel Morales; Stanley L. Hazen; W. H. Wilson Tang; Sathyamangla V. N...
• Keywords: Subclass; Arrestin

Dysregulation of immune responses has been linked to the generation immunoglobulin G (IgG) autoantibodies that target human β1ARs and contribute deleterious cardiac outcomes. Given benefits β-blockers observed in patients harboring IgG3 subclass autoantibodies, we investigated role these β1AR function. Serum purified IgG3(+) from with onset cardiomyopathy were tested using embryonic kidney (HEK) 293 cells expressing β1ARs. Unexpectedly, pretreatment serum or impaired dobutamine-mediated adenylate cyclase (AC) activity cyclic adenosine monophosphate (cAMP) while enhancing biased β-arrestin recruitment Extracellular Regulated Kinase (ERK) activation. In contrast, β-blocker metoprolol increased AC cAMP presence autoantibodies. Because are specific β1ARs, non-failing hearts used as an endogenous system determine their ability bias signaling. Consistently, activity, reflecting toward G-protein coupling. Importantly, they did not alter β2AR Thus, autoantibody biases coupling impairing agonist-mediated activation but promoting G-protein-independent ERK This phenomenon may underlie beneficial outcomes