α_1B/D-adrenoceptors regulate chemokine receptor–mediated leukocyte migration via formation of heteromeric receptor complexes

Abstract

Significance Here we show that most chemokine receptors (CRs) form heteromeric complexes with α 1 -adrenergic receptors (ARs) in recombinant systems and that such heteromers are detectable in human monocytes and in the human monocytic leukemia cell line THP-1. Furthermore, we provide evidence that α 1B/D -ARs control the function of their CR heteromerization partners. Our findings suggest that heteromeric complexes between α 1B/D -ARs and CRs are necessary for normal function of CR heteromerization partners, indicate receptor heteromerization as a molecular mechanism by which stress hormones regulate leukocyte trafficking in health and disease, and offer opportunities to modulate leukocyte and/or cancer cell trafficking in disease processes.

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

“…1C, right). These findings confirm our previous observations that recombinant and endogenously expressed a 1B -AR and CCR2 constitutively heteromerize, and suggest that such heteromers are also expressed in human vascular smooth muscle [9].…”

“…1B), respectively. Consistent with our previous observations, BRET between a 1b -AR and CCR2 showed hyperbolic progressions with increasing energy acceptor: donor ratios in each energy acceptor: donor configuration, suggesting constitutive heteromerization [9,22]. As expected, BRET between a 1b -AR-RLuc or CCR2-RLuc and mGlu 1 R-YFP or YFP was low and increased linearly with increasing energy acceptor: donor ratios, which is consistent with nonspecific bystander BRET [9][10][11].…”

“…Human vascular smooth muscle cells were transfected with NT siRNA or CCR2 siRNA at a final concentration of 1 lM using Accell Delivery Media (GE Dharmacon) as previously described [9,14,16,20].…”

“…Recently, we provided evidence that most human chemokine receptors can form heteromers with α 1 ‐adrenergic receptors (ARs) in recombinant systems and that such heteromers, including CCR2:α 1B ‐AR heteromers, are detectable in human leukocytes, through which α 1B ‐AR regulate chemokine receptor function [9]. Whether CCR2:α 1B ‐AR heteromerization occurs in human vascular smooth muscle and affects α 1B ‐AR signaling, however, is unknown.…”

“…which a 1B -AR regulate chemokine receptor function [9]. Whether CCR2:a 1B -AR heteromerization occurs in human vascular smooth muscle and affects a 1B -AR signaling, however, is unknown.…”