Molecular determinants on extracellular loop domains that dictate interaction between β-arrestin and human APJ receptor.

The human APJ receptor (APJR), activated by apelin isoforms, regulates cardiovascular functions and fluid homeostasis. Understanding its structure-function relationship is crucial for a comprehensive knowledge of signalling aberrations that cause several physiological disorders. Here, we demonstrate the influence of extracellular loop (ECL) domains in the mechanism of β-arrestin-mediated signalling from human APJR: Apelin system. Alanine mutations of evolutionarily conserved residues were characterized using receptor internalization, β-arrestin pull-down, Akt phosphorylation and cell migration assay. C281A and ²⁶⁸ KTL²⁷⁰ -AAA in ECL3 were deficient in all assays, whereas ¹⁸³ MDYS¹⁸⁶ -AAAA mutant in ECL2 showed impaired β-arrestin-mediated signalling but demonstrated G_i -dependent cell migration. Our findings establish that conserved residues in the extracellular domain play a prominent role in modulating receptor interactions with the β-arrestin signalling cascade.

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