Asymmetrical ligand-induced cross-regulation of chemokine (C-X-C motif) receptor 4 by alpha1-adrenergic receptors at the heteromeric receptor complex Journal Article

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Authors: Gao, X; Albee, L. J.; Volkman, B. F.; Gaponenko, V.; Majetschak, M
Article Title: Asymmetrical ligand-induced cross-regulation of chemokine (C-X-C motif) receptor 4 by alpha1-adrenergic receptors at the heteromeric receptor complex
Abstract: Recently, we reported that chemokine (C-X-C motif) receptor (CXCR)4 and atypical chemokine receptor 3 regulate alpha1-adrenergic receptors (alpha1-AR) through the formation of hetero-oligomeric complexes. Whether alpha1-ARs also regulate chemokine receptor function within such heteromeric receptor complexes is unknown. We observed that activation of alpha1b-AR within the alpha1b-AR:CXCR4 heteromeric complex leads to cross-recruitment of beta-arrestin2 to CXCR4, which could not be inhibited with AMD3100. Activation of CXCR4 did not cross-recruit beta-arrestin2 to alpha1b-AR. A peptide analogue of transmembrane domain 2 of CXCR4 interfered with alpha1b-AR:CXCR4 heteromerization and inhibited alpha1b-AR-mediated beta-arrestin2 cross-recruitment. Phenylephrine (PE) induced internalization of CXCR4 in HEK293 cells co-expressing CXCR4 and alpha1b-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 alpha1-adrenergic receptors within the heteromeric receptor complex. Our findings provide mechanistic insights into the function of alpha1-AR:CXCR4 heteromers and suggest alternative approaches to modulate CXCR4 in disease conditions.
Journal Title: Scientific reports
Volume: 8
Issue: 1
ISSN: 2045-2322; 2045-2322
Publisher: Unknown  
Journal Place: England
Date Published: 2018
Start Page: 2730
End Page: 018-21096-4
Language: eng
DOI/URL:

10.1038/s41598-018-21096-4
Notes: LR: 20180216; GR: R01 CA188427/CA/NCI NIH HHS/United States; GR: R01 GM107495/GM/NIGMS NIH HHS/United States; JID: 101563288; 2017/09/26 00:00 [received]; 2018/01/30 00:00 [accepted]; 2018/02/11 06:00 [entrez]; 2018/02/11 06:00 [pubmed]; 2018/02/11 06:00 [medline]; epublish