Authors: | Albee, L. J.; LaPorte, H. M.; Gao, X; Eby, J. M.; Cheng, Y. H.; Nevins, A. M.; Volkman, B. F.; Gaponenko, V.; Majetschak, M |
Article Title: | Identification and functional characterization of arginine vasopressin receptor 1A : atypical chemokine receptor 3 heteromers in vascular smooth muscle |
Abstract: | Recent observations suggest that atypical chemokine receptor (ACKR)3 and chemokine (C-X-C motif) receptor (CXCR)4 regulate human vascular smooth muscle function through hetero-oligomerization with alpha1-adrenoceptors. Here, we show that ACKR3 also regulates arginine vasopressin receptor (AVPR)1A. We observed that ACKR3 agonists inhibit arginine vasopressin (aVP)-induced inositol trisphosphate (IP3) production in human vascular smooth muscle cells (hVSMCs) and antagonize aVP-mediated constriction of isolated arteries. Proximity ligation assays, co-immunoprecipitation and bioluminescence resonance energy transfer experiments suggested that recombinant and endogenous ACKR3 and AVPR1A interact on the cell surface. Interference with ACKR3 : AVPR1A heteromerization using siRNA and peptide analogues of transmembrane domains of ACKR3 abolished aVP-induced IP3 production. aVP stimulation resulted in beta-arrestin 2 recruitment to AVPR1A and ACKR3. While ACKR3 activation failed to cross-recruit beta-arrestin 2 to AVPR1A, the presence of ACKR3 reduced the efficacy of aVP-induced beta-arrestin 2 recruitment to AVPR1A. AVPR1A and ACKR3 co-internalized upon agonist stimulation in hVSMC. These data suggest that AVPR1A : ACKR3 heteromers are constitutively expressed in hVSMC, provide insights into molecular events at the heteromeric receptor complex, and offer a mechanistic basis for interactions between the innate immune and vasoactive neurohormonal systems. Our findings suggest that ACKR3 is a regulator of vascular smooth muscle function and a possible drug target in diseases associated with impaired vascular reactivity. |
Journal Title: | Open biology |
Volume: | 8 |
Issue: | 1 |
ISSN: | 2046-2441; 2046-2441 |
Publisher: | The Authors |
Journal Place: | England |
Date Published: | 2018 |
Start Page: | 10.1098/rsob.170207 |
Language: | eng |
DOI/URL: |
170207 |
Notes: | LR: 20180307; CI: (c) 2018; GR: R01 CA188427/CA/NCI NIH HHS/United States; JID: 101580419; OTO: NOTNLM; 2017/08/30 00:00 [received]; 2018/01/08 00:00 [accepted]; 2018/02/02 06:00 [entrez]; 2018/02/02 06:00 [pubmed]; 2018/02/02 06:00 [medline]; ppublish |