RGD Reference Report - Identification and functional characterization of arginine vasopressin receptor 1A : atypical chemokine receptor 3 heteromers in vascular smooth muscle. - Rat Genome Database

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Identification and functional characterization of arginine vasopressin receptor 1A : atypical chemokine receptor 3 heteromers in vascular smooth muscle.

Authors: Albee, Lauren J  LaPorte, Heather M  Gao, Xianlong  Eby, Jonathan M  Cheng, You-Hong  Nevins, Amanda M  Volkman, Brian F  Gaponenko, Vadim  Majetschak, Matthias 
Citation: Albee LJ, etal., Open Biol. 2018 Jan;8(1). pii: rsob.170207. doi: 10.1098/rsob.170207.
RGD ID: 14697727
Pubmed: PMID:29386406   (View Abstract at PubMed)
PMCID: PMC5795052   (View Article at PubMed Central)
DOI: DOI:10.1098/rsob.170207   (Journal Full-text)

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 α1-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 β-arrestin 2 recruitment to AVPR1A and ACKR3. While ACKR3 activation failed to cross-recruit β-arrestin 2 to AVPR1A, the presence of ACKR3 reduced the efficacy of aVP-induced β-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.

Objects referenced in this article
Gene Ackr3 atypical chemokine receptor 3 Rattus norvegicus
Gene Cxcr4 C-X-C motif chemokine receptor 4 Rattus norvegicus

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