New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle
AbstractRecent 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
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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.
Evans AE, Tripathi A, LaPorte HM, Brueggemann LI, Singh AK, Albee LJ, Byron KL, Tarasova NI, Volkman BF, Cho TY, Gaponenko V, Majetschak M. New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle. International Journal of Molecular Sciences. 2016; 17(6):971.Chicago/Turabian Style
Evans, Ann E.; Tripathi, Abhishek; LaPorte, Heather M.; Brueggemann, Lioubov I.; Singh, Abhay K.; Albee, Lauren J.; Byron, Kenneth L.; Tarasova, Nadya I.; Volkman, Brian F.; Cho, Thomas Y.; Gaponenko, Vadim; Majetschak, Matthias. 2016. "New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle." Int. J. Mol. Sci. 17, no. 6: 971.
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