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Int. J. Mol. Sci. 2016, 17(6), 971; doi:10.3390/ijms17060971

New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle

1
Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL 60153, USA
2
Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL 60153, USA
3
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1100 South Grand Blvd., St. Louis, MO 63104, USA
4
Cancer and Inflammation Program, National Cancer Institute, PO Box B, Frederick, MD 21702-1201, USA
5
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
6
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S Ashland, Chicago, IL 60607, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Kathleen Van Craenenbroeck
Received: 28 April 2016 / Revised: 7 June 2016 / Accepted: 13 June 2016 / Published: 20 June 2016
(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)
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Abstract

Recent evidence suggests that C-X-C chemokine receptor type 4 (CXCR4) heteromerizes with α1A/B-adrenoceptors (AR) and atypical chemokine receptor 3 (ACKR3) and that CXCR4:α1A/B-AR heteromers are important for α1-AR function in vascular smooth muscle cells (VSMC). Structural determinants for CXCR4 heteromerization and functional consequences of CXCR4:α1A/B-AR heteromerization in intact arteries, however, remain unknown. Utilizing proximity ligation assays (PLA) to visualize receptor interactions in VSMC, we show that peptide analogs of transmembrane-domain (TM) 2 and TM4 of CXCR4 selectively reduce PLA signals for CXCR4:α1A-AR and CXCR4:ACKR3 interactions, respectively. While both peptides inhibit CXCL12-induced chemotaxis, only the TM2 peptide inhibits phenylephrine-induced Ca2+-fluxes, contraction of VSMC and reduces efficacy of phenylephrine to constrict isolated arteries. In a Cre-loxP mouse model to delete CXCR4 in VSMC, we observed 60% knockdown of CXCR4. PLA signals for CXCR4:α1A/B-AR and CXCR4:ACKR3 interactions in VSMC, however, remained constant. Our observations point towards TM2/4 of CXCR4 as possible contact sites for heteromerization and suggest that TM-derived peptide analogs permit selective targeting of CXCR4 heteromers. A molecular dynamics simulation of a receptor complex in which the CXCR4 homodimer interacts with α1A-AR via TM2 and with ACKR3 via TM4 is presented. Our findings further imply that CXCR4:α1A-AR heteromers are important for intrinsic α1-AR function in intact arteries and provide initial and unexpected insights into the regulation of CXCR4 heteromerization in VSMC. View Full-Text
Keywords: atypical chemokine receptor 3; (C-X-C motif) receptor 7; adrenergic receptor; vascular function; blood pressure; G protein-coupled receptor; receptor heteromer; structural modeling atypical chemokine receptor 3; (C-X-C motif) receptor 7; adrenergic receptor; vascular function; blood pressure; G protein-coupled receptor; receptor heteromer; structural modeling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Evans, A.E.; Tripathi, A.; LaPorte, H.M.; Brueggemann, L.I.; Singh, A.K.; Albee, L.J.; Byron, K.L.; Tarasova, N.I.; Volkman, B.F.; Cho, T.Y.; Gaponenko, V.; Majetschak, M. New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle. Int. J. Mol. Sci. 2016, 17, 971.

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