G protein activation via chemokine (C‐X‐C motif) receptor 4 and α1b‐adrenoceptor is ligand and heteromer‐dependent

Abstract

It is unknown whether heteromerization between chemokine (C‐X‐C motif) receptor 4 (CXCR4), atypical chemokine receptor 3 (ACKR3) and α1b‐adrenoceptor (α1b‐AR) influences effects of the CXCR4/ACKR3 agonist chemokine (C‐X‐C motif) ligand 12 (CXCL12) and the noncognate CXCR4 agonist ubiquitin on agonist‐promoted G protein activation. We provide biophysical evidence that both ligands stimulate CXCR4‐mediated Gαi activation. Unlike CXCL12, ubiquitin fails to recruit β‐arrestin. Both ligands differentially modulate the conformation of CXCR4:ACKR3 heterodimers and its propensity to hetero‐trimerize with α1b‐AR. CXCR4:ACKR3 heterodimerization reduces the potency of CXCL12, but not of ubiquitin, to activate Gαi. Ubiquitin enhances phenylephrine‐stimulated α1b‐AR‐promoted Gαq activation from hetero‐oligomers comprising CXCR4. CXCL12 enhances phenylephrine‐stimulated α1b‐AR‐promoted Gαq activation from CXCR4:α1b‐AR heterodimers and reduces phenylephrine‐stimulated α1b‐AR‐promoted Gαq activation from ACKR3 comprising heterodimers and trimers. Our findings suggest heteromer and ligand‐dependent functions of the receptor partners.