alpha1-Adrenergic Receptors Function Within Hetero-Oligomeric Complexes With Atypical Chemokine Receptor 3 and Chemokine (C-X-C motif) Receptor 4 in Vascular Smooth Muscle Cells Journal Article

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Authors: Albee, L. J.; Eby, J. M.; Tripathi, A; LaPorte, H. M.; Gao, X; Volkman, B. F.; Gaponenko, V.; Majetschak, M
Article Title: alpha1-Adrenergic Receptors Function Within Hetero-Oligomeric Complexes With Atypical Chemokine Receptor 3 and Chemokine (C-X-C motif) Receptor 4 in Vascular Smooth Muscle Cells
Abstract: BACKGROUND: Recently, we provided evidence that alpha1-adrenergic receptors (ARs) in vascular smooth muscle are regulated by chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor 3 (ACKR3). While we showed that CXCR4 controls alpha1-ARs through formation of heteromeric receptor complexes in human vascular smooth muscle cells (hVSMCs), the molecular basis underlying cross-talk between ACKR3 and alpha1-ARs is unknown. METHODS AND RESULTS: We show that ACKR3 agonists inhibit inositol trisphosphate production in hVSMCs on stimulation with phenylephrine. In proximity ligation assays and co-immunoprecipitation experiments, we observed that recombinant and endogenous ACKR3 form heteromeric complexes with alpha1A/B/D-AR. While small interfering RNA knockdown of ACKR3 in hVSMCs reduced alpha1B/D-AR:ACKR3, CXCR4:ACKR3, and alpha1B/D-AR:CXCR4 complexes, small interfering RNA knockdown of CXCR4 reduced alpha1B/D-AR:ACKR3 heteromers. Phenylephrine-induced inositol trisphosphate production from hVSMCs was abolished after ACKR3 and CXCR4 small interfering RNA knockdown. Peptide analogs of transmembrane domains 2/4/7 of ACKR3 showed differential effects on heteromerization between ACKR3, alpha1A/B/D-AR, and CXCR4. While the transmembrane domain 2 peptide interfered with alpha1B/D-AR:ACKR3 and CXCR4:ACKR3 heteromerization, it increased heteromerization between CXCR4 and alpha1A/B-AR. The transmembrane domain 2 peptide inhibited ACKR3 but did not affect alpha1b-AR in beta-arrestin recruitment assays. Furthermore, the transmembrane domain 2 peptide inhibited phenylephrine-induced inositol trisphosphate production in hVSMCs and attenuated phenylephrine-induced constriction of mesenteric arteries. CONCLUSIONS: alpha1-ARs form hetero-oligomeric complexes with the ACKR3:CXCR4 heteromer, which is required for alpha1B/D-AR function, and activation of ACKR3 negatively regulates alpha1-ARs. G protein-coupled receptor hetero-oligomerization is a dynamic process, which depends on the relative abundance of available receptor partners. Endogenous alpha1-ARs function within a network of hetero-oligomeric receptor complexes.
Journal Title: Journal of the American Heart Association
Volume: 6
Issue: 8
ISSN: 2047-9980; 2047-9980
Publisher: The Authors. Published on behalf of the American Heart Association, Inc., by Wiley  
Journal Place: England
Date Published: 2017
Start Page: 10.1161/JAHA.117.006575
Language: eng
DOI/URL:

e006575
Notes: LR: 20171010; CI: (c) 2017; GR: R01 AI058072/AI/NIAID NIH HHS/United States; JID: 101580524; OTO: NOTNLM; epublish