Heteromerization between alpha(1B)-adrenoceptor and chemokine (C-C motif) receptor 2 biases alpha(1B)-adrenoceptor signaling: Implications for vascular function

Previously, we reported that chemokine (C-C motif) receptor 2 (CCR2) heteromerizes with alpha(1B)-adrenoceptor (alpha(1B)-AR) in leukocytes, through which alpha(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:alpha(1b)-AR heteromers. Proximity ligation assays detected CCR2:alpha(1B)-AR heteromers in hVSMCs and human mesenteric arteries. CCR2:alpha(1B)-AR heteromerization per se enhanced alpha(1B)-AR-mediated G alpha(q)-coupling. Chemokine (C-C motif) ligand 2 (CCL2) binding to CCR2 inhibited G alpha(q) activation via alpha(1B)-AR, cross-recruited D-arrestin to and induced internalization of alpha(1B)-AR in recombinant systems and in hVSMCs. Our findings suggest that CCR2 within CCR2:alpha(1B)-AR heteromers biases alpha(1B)-AR signaling and provide a mechanism for previous observations suggesting a role for CCL2/CCR2 in the regulation of cardiovascular function.