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

International Journal of Molecular Sciences

Matthias Majetschak¹  Heather M. LaPorte¹  Ann E. Evans¹  Lauren J. Albee¹  Abhishek Tripathi¹  Nadya I. Tarasova²  Vadim Gaponenko³  Brian F. Volkman⁴  Lioubov I. Brueggemann⁵  Thomas Yoonsang Cho⁶  Kenneth L. Byron⁶  Abhay Kumar Singh⁶ 

[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;Cancer and Inflammation Program, National Cancer Institute, PO Box B, Frederick, MD 21702-1201, USA;Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S Ashland, Chicago, IL 60607, USA;Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA;Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL 60153, USA;Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1100 South Grand Blvd., St. Louis, MO 63104, USA;

关键词: atypical chemokine receptor 3;    (C-X-C motif) receptor 7;    adrenergic receptor;    vascular function;    blood pressure;    G protein-coupled receptor;    receptor heteromer;    structural modeling;   

DOI  :  10.3390/ijms17060971

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown