Heteromerization between α1B -adrenoceptor and chemokine (C-C motif) receptor 2 biases α1B -adrenoceptor signaling: Implications for vascular function

Abstract

Previously, we reported that chemokine (C-C motif) receptor 2 (CCR2) heteromerizes with α_1B -adrenoceptor (α_1B -AR) in leukocytes, through which α_1B -AR controls CCR2. Whether such heteromers are expressed in human vascular smooth muscle cells (hVSMCs) is unknown. Bioluminescence resonance energy transfer confirmed formation of recombinant CCR2:α_1b -AR heteromers. Proximity ligation assays detected CCR2:α_1B -AR heteromers in hVSMCs and human mesenteric arteries. CCR2:α_1B -AR heteromerization per se enhanced α_1B -AR-mediated Gα_q -coupling. Chemokine (C-C motif) ligand 2 (CCL2) binding to CCR2 inhibited Gα_q activation via α_1B -AR, cross-recruited β-arrestin to and induced internalization of α_1B -AR in recombinant systems and in hVSMCs. Our findings suggest that CCR2 within CCR2:α_1B -AR heteromers biases α_1B -AR signaling and provide a mechanism for previous observations suggesting a role for CCL2/CCR2 in the regulation of cardiovascular function.

Keywords: Ca2+-fluxes; G protein coupled receptor heteromers; Gαq coupling; bioluminescence resonance energy transfer G protein biosensors; inositol trisphosphate; receptor internalization; β-arrestin.