Autoantibodies as Endogenous Modulators of GPCR Signaling. (March 2021) - Skiba, Meredith A.
Abstract : Endogenous self-reactive autoantibodies (AAs) recognize a range of G-protein-coupled receptors (GPCRs). They are frequently associated with cardiovascular, neurological, and autoimmune disorders, and in some cases directly impact disease progression. Many GPCR AAs modulate receptor signaling, but molecular details of their modulatory activity are not well understood. Technological advances have provided insight into GPCR biology, which now facilitates deeper understanding of GPCR AA function at the molecular level. Most GPCR AAs are allosteric modulators and exhibit a broad range of pharmacological properties, altering both receptor signaling and trafficking. Understanding GPCR AAs is not only important for defining how these unusual GPCR modulators function in disease, but also provides insight into the potential use and limitations of using therapeutic antibodies to modulate GPCR signaling. Highlights: Self-reactive antibodies (autoantibodies or AAs) are produced when there is a breakdown in the immune system's self-tolerance mechanisms and have been detected for 26 G-protein-coupled receptors (GPCRs). Despite considerable interest in therapeutic modulation of GPCRs with antibodies, little is known about the molecular function of AAs. The vast majority of AAs described to date are functional and activate GPCR signaling, uncoupling receptors from endogenous signaling networks. Such modulation of signaling is often deleterious and many GPCR AAs are either known to be pathogenic or associated with disease. AAs act allosterically and possess unique pharmacological properties, which often diverge from orthosteric agonists. A dimeric antibody is often required for AA-induced receptor activation, suggesting that AAs may invoke an activation mechanism distinct from orthosteric agonists.