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New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle. Int J Mol Sci 2016 Jun 20;17(5)

Date

06/23/2016

Pubmed ID

27331810

Pubmed Central ID

PMC4926503

DOI

10.3390/ijms17060971

Scopus ID

2-s2.0-85015592466   12 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: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 Ca(2+)-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.

Author List

Evans AE, Tripathi A, LaPorte HM, Brueggemann LI, Singh AK, Albee LJ, Byron KL, Tarasova NI, Volkman BF, Cho TY, Gaponenko V, Majetschak M

Author

Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Binding Sites
Calcium
Cell Line
Cells, Cultured
Female
Humans
Male
Mice
Molecular Dynamics Simulation
Muscle, Smooth, Vascular
Protein Binding
Protein Multimerization
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, alpha-1
Receptors, CXCR
Receptors, CXCR4
jenkins-FCD Prod-444 eb4ebd1a08581aba961d3befd3b851a3c3ec6b46