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Asymmetrical ligand-induced cross-regulation of chemokine (C-X-C motif) receptor 4 by α-adrenergic receptors at the heteromeric receptor complex. Sci Rep 2018 02 09;8(1):2730

Date

02/11/2018

Pubmed ID

29426850

Pubmed Central ID

PMC5807542

DOI

10.1038/s41598-018-21096-4

Scopus ID

2-s2.0-85053764631   3 Citations

Abstract

Recently, we reported that chemokine (C-X-C motif) receptor (CXCR)4 and atypical chemokine receptor 3 regulate α-adrenergic receptors (α-AR) through the formation of hetero-oligomeric complexes. Whether α-ARs also regulate chemokine receptor function within such heteromeric receptor complexes is unknown. We observed that activation of α-AR within the α-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-AR. A peptide analogue of transmembrane domain 2 of CXCR4 interfered with α-AR:CXCR4 heteromerization and inhibited α-AR-mediated β-arrestin2 cross-recruitment. Phenylephrine (PE) induced internalization of CXCR4 in HEK293 cells co-expressing CXCR4 and α-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 (IC: 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 α-adrenergic receptors within the heteromeric receptor complex. Our findings provide mechanistic insights into the function of α-AR:CXCR4 heteromers and suggest alternative approaches to modulate CXCR4 in disease conditions.

Author List

Gao X, Albee LJ, Volkman BF, Gaponenko V, Majetschak M

Author

Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adrenergic alpha-1 Receptor Agonists
Cell Membrane
Cells, Cultured
Chemotaxis
Humans
Ligands
Myocytes, Smooth Muscle
Phenylephrine
Protein Binding
Receptors, Adrenergic, alpha-1
Receptors, CXCR4
Signal Transduction
beta-Arrestins
jenkins-FCD Prod-444 eb4ebd1a08581aba961d3befd3b851a3c3ec6b46