New insights into mechanisms and functions of chemokine (C-X-C motif) receptor 4 heteromerization in vascular smooth muscle

Ann E. Evans, Abhishek Tripathi, Heather M. LaPorte, Lioubov I. Brueggemann, Abhay Kumar Singh, Lauren J. Albee, Kenneth L. Byron, Nadya I. Tarasova, Brian F. Volkman, Thomas Yoonsang Cho, Vadim Gaponenko, Matthias Majetschak

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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: α 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.

Original languageEnglish
Article number971
JournalInternational journal of molecular sciences
Volume17
Issue number6
DOIs
StatePublished - Jun 20 2016

Keywords

  • (C-X-C motif) receptor 7
  • Adrenergic receptor
  • Atypical chemokine receptor 3
  • Blood pressure
  • G protein-coupled receptor
  • Receptor heteromer
  • Structural modeling
  • Vascular function

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