Asymmetrical ligand-induced cross-regulation of chemokine (C-X-C motif) receptor 4 by α₁-adrenergic receptors at the heteromeric receptor complex.

Recently, we reported that chemokine (C-X-C motif) receptor (CXCR)4 and atypical chemokine receptor 3 regulate α₁-adrenergic receptors (α₁-AR) through the formation of hetero-oligomeric complexes. Whether α₁-ARs also regulate chemokine receptor function within such heteromeric receptor complexes is unknown. We observed that activation of α_1b-AR within the α_1b-AR:CXCR4 heteromeric complex leads to cross-recruitment of β-arrestin2 to CXCR4, which could not be inhibited with AMD3100. Activation of CXCR4 did not cross-recruit β-arrestin2 to α_1b-AR. A peptide analogue of transmembrane domain 2 of CXCR4 interfered with α_1b-AR:CXCR4 heteromerization and inhibited α_1b-AR-mediated β-arrestin2 cross-recruitment. Phenylephrine (PE) induced internalization of CXCR4 in HEK293 cells co-expressing CXCR4 and α_1b-AR and of endogenous CXCR4 in human vascular smooth muscle cells (hVSMC). The latter was detectable despite blockade of CXCR4 with the neutralizing antibody 12G5. hVSMC migrated towards CXCL12 and PE, but not towards a combination of CXCL12 and PE. PE inhibited CXCL12-induced chemotaxis of hVSMC (IC₅₀: 77 ± 30 nM). Phentolamine cross-inhibited CXCL12-induced chemotaxis of hVSMC, whereas AMD3100 did not cross-inhibit PE-induced chemotaxis. These data provide evidence for asymmetrical cross-regulation of CXCR4 by α₁-adrenergic receptors within the heteromeric receptor complex. Our findings provide mechanistic insights into the function of α₁-AR:CXCR4 heteromers and suggest alternative approaches to modulate CXCR4 in disease conditions.

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