Molecular dissection of ligand mediated C3aR1 signaling function significance for lipolysis and other cellular functions

Abstract

G protein-coupled receptors (GPCRs) are critically involved in metabolic functions, and are leading druggable targets for pharmacotherapies. However, many GPCRs are still untapped for their therapeutic potential due to poor understanding of specific signaling properties. The complement C3a receptor 1 (C3aR1) has been extensively studied for its physiological role in C3a-mediated anaphylaxis/inflammation, and in TLQP-21-mediated lipolysis, but direct evidence for these two ligands functional relevance and signal transduction mechanisms are still limited. Because the complement system has a key role in innate immunity, connects the innate and the adaptive immune systems, and can modulate metabolic diseases, it has been a target of pharmacotherapies and therapeutic interventions, however promising results never translated into clinical applications thus far. By focusing on ligand mediated C3aR1 signaling, we aim to create knowledge that can serve to develop drug-like compounds that can be used as effective and safe therapeutic for obesity- and inflammatory-related conditions. To do so, we aimed: i) to understand how TLQP-21/C3a interacts with C3aR1 and potentiates adrenergic induced lipolysis; ii) to understand how TLQP-21 and C3a differentially activate C3aR1 in an effort to explain their different physiology and pharmacology; and iii) to rationally design a series of peptides derivatives of TLQP-21 in order to create a compound with therapeutic potential for further development.