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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. [ABSTRACT FROM AUTHOR]

Previously, we reported that chemokine (C‐C motif) receptor 2 (CCR2) heteromerizes with α1B‐adrenoceptor (α1B‐AR) in leukocytes, through which α1B‐AR controls CCR2. Whether such heteromers are expressed in human vascular smooth muscle cells (hVSMCs) is unknown. Bioluminescence resonance energy transfer confirmed formation of recombinant CCR2:α1b‐AR heteromers. Proximity ligation assays detected CCR2:α1B‐AR heteromers in hVSMCs and human mesenteric arteries. CCR2:α1B‐AR heteromerization per se enhanced α1B‐AR‐mediated Gαq‐coupling. Chemokine (C‐C motif) ligand 2 (CCL2) binding to CCR2 inhibited Gαq activation via α1B‐AR, cross‐recruited β‐arrestin to and induced internalization of α1B‐AR in recombinant systems and in hVSMCs. Our findings suggest that CCR2 within CCR2:α1B‐AR heteromers biases α1B‐AR signaling and provide a mechanism for previous observations suggesting a role for CCL2/CCR2 in the regulation of cardiovascular function. [ABSTRACT FROM AUTHOR]

It is unknown whether heteromerization between chemokine (C-X-C motif) receptor 4 (CXCR4), atypical chemokine receptor 3 (ACKR3) and α 1b -adrenoceptor (α 1b -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 α 1b -AR. CXCR4:ACKR3 heterodimerization reduces the potency of CXCL12, but not of ubiquitin, to activate Gαi. Ubiquitin enhances phenylephrine-stimulated α 1b -AR-promoted Gαq activation from hetero-oligomers comprising CXCR4. CXCL12 enhances phenylephrine-stimulated α 1b -AR-promoted Gαq activation from CXCR4:α 1b -AR heterodimers and reduces phenylephrine-stimulated α 1b -AR-promoted Gαq activation from ACKR3 comprising heterodimers and trimers. Our findings suggest heteromer and ligand-dependent functions of the receptor partners., (© 2023 Federation of European Biochemical Societies.)

Previously, we reported that chemokine (C-C motif) receptor 2 (CCR2) heteromerizes with α 1B -adrenoceptor (α 1B -AR) in leukocytes, through which α 1B -AR controls CCR2. Whether such heteromers are expressed in human vascular smooth muscle cells (hVSMCs) is unknown. Bioluminescence resonance energy transfer confirmed formation of recombinant CCR2:α 1b -AR heteromers. Proximity ligation assays detected CCR2:α 1B -AR heteromers in hVSMCs and human mesenteric arteries. CCR2:α 1B -AR heteromerization per se enhanced α 1B -AR-mediated Gα q -coupling. Chemokine (C-C motif) ligand 2 (CCL2) binding to CCR2 inhibited Gα q activation via α 1B -AR, cross-recruited β-arrestin to and induced internalization of α 1B -AR in recombinant systems and in hVSMCs. Our findings suggest that CCR2 within CCR2:α 1B -AR heteromers biases α 1B -AR signaling and provide a mechanism for previous observations suggesting a role for CCL2/CCR2 in the regulation of cardiovascular function., (© 2022 Federation of European Biochemical Societies.)