Heteromerization of chemokine (C-X-C motif) receptor 4 with alpha1A/B-adrenergic receptors controls alpha1-adrenergic receptor function Journal Article


Authors: Tripathi, A; Vana, P. G.; Chavan, T. S.; Brueggemann, L. I.; Byron, K. L.; Tarasova, N. I.; Volkman, B. F.; Gaponenko, V.; Majetschak, M
Article Title: Heteromerization of chemokine (C-X-C motif) receptor 4 with alpha1A/B-adrenergic receptors controls alpha1-adrenergic receptor function
Abstract: Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regulation of blood pressure through interactions with alpha1-adrenergic receptors (ARs) in vascular smooth muscle. The underlying molecular mechanisms, however, are unknown. Using proximity ligation assays to visualize single-molecule interactions, we detected that alpha1A/B-ARs associate with CXCR4 on the cell surface of rat and human vascular smooth muscle cells (VSMC). Furthermore, alpha1A/B-AR could be coimmunoprecipitated with CXCR4 in a HeLa expression system and in human VSMC. A peptide derived from the second transmembrane helix of CXCR4 induced chemical shift changes in the NMR spectrum of CXCR4 in membranes, disturbed the association between alpha1A/B-AR and CXCR4, and inhibited Ca2+ mobilization, myosin light chain (MLC) 2 phosphorylation, and contraction of VSMC upon alpha1-AR activation. CXCR4 silencing reduced alpha1A/B-AR:CXCR4 heteromeric complexes in VSMC and abolished phenylephrine-induced Ca2+ fluxes and MLC2 phosphorylation. Treatment of rats with CXCR4 agonists (CXCL12, ubiquitin) reduced the EC50 of the phenylephrine-induced blood pressure response three- to fourfold. These observations suggest that disruption of the quaternary structure of alpha1A/B-AR:CXCR4 heteromeric complexes by targeting transmembrane helix 2 of CXCR4 and depletion of the heteromeric receptor complexes by CXCR4 knockdown inhibit alpha1-AR-mediated function in VSMC and that activation of CXCR4 enhances the potency of alpha1-AR agonists. Our findings extend the current understanding of the molecular mechanisms regulating alpha1-AR and provide an example of the importance of G protein-coupled receptor (GPCR) heteromerization for GPCR function. Compounds targeting the alpha1A/B-AR:CXCR4 interaction could provide an alternative pharmacological approach to modulate blood pressure.
Keywords: Surgery; Ubiquitin; Blood Pressure; CXCL12; AMD3100; phenylephrine
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 112
Issue: 13
ISSN: 1091-6490; 0027-8424
Publisher: Unknown  
Date Published: 2015
Start Page: E1659
End Page: E1668
Language: ENG
DOI/URL:
Notes: LR: 20150317; JID: 7505876; OTO: NOTNLM; aheadofprint