Heterodimerization of apelin receptor and neurotensin receptor 1 induces phosphorylation of ERK1/2and cell proliferationviaGαq-mediated mechanism

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Bai, Bo ; Cai, Xin ; Jiang, Yunlu ; Karteris, Emmanouil ; Chen, Jing (2014)
  • Publisher: Wiley-Blackwell Publishing, Inc
  • Related identifiers: doi: 10.1111/jcmm.12404
  • Subject: QP
    mesheuropmc: hormones, hormone substitutes, and hormone antagonists

Dimerization of G protein-coupled receptors (GPCRs) is crucial for receptor function including agonist affinity, efficacy, trafficking and specificity of signal transduction, including G protein coupling. Emerging data suggest that the cardiovascular system is the main target of apelin, which exerts an overall neuroprotective role, and is a positive regulator of angiotensin-converting enzyme 2 (ACE2) in heart failure. Moreover, ACE2 cleaves off C-terminal residues of vasoactive peptides including apelin-13, and neurotensin that activate the apelin receptor (APJ) and neurotensin receptor 1 (NTSR1) respectively, that belong to the A class of GPCRs. Therefore, based on the similar mode of modification by ACE2 at peptide level, the homology at amino acid level and the capability of forming dimers with other GPCRs, we have been suggested that APJ and NTSR1 can form a functional heterodimer. Using co-immunoprecipitation, BRET and FRET, we provided conclusive evidence of heterodimerization between APJ and NTSR1 in a constitutive and induced form. Upon agonist stimulation, hetrodimerization enhanced ERK1/2 activation and increased proliferation via activation of Gq α-subunits. These novel data provide evidence for a physiological role of APJ/NTSR1 heterodimers in terms of ERK1/2 activation and increased intracellular calcium and induced cell proliferation and provide potential new pharmaceutical targets for cardiovascular disease.
  • References (26)
    26 references, page 1 of 3

    Sato T, Suzuki T, Watanabe H, et al. Apelin is a positive regulator of ACE2 in failing hearts. J Clin Invest. 2013; 123: 5203-11.

    Meng Y, Yu CH, Li W, et al. Angiotensinconverting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-kappaB pathway. Am J Respir Cell Mol Biol. 2014; 50: 723-36.

    Danilczyk U, Penninger JM. Angiotensinconverting enzyme II in the heart and the kidney. Circ Res. 2006; 98: 463-71.

    Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002; 277: 14838-43.

    Trends Pharmacol Sci. 2014; 35: 247-55.

    The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. J Endocrinol. 2013; 219: R13-35.

    Li Y, Chen J, Bai B, et al. Heterodimerization of human apelin and kappa opioid receptors: roles in signal transduction. Cell Signal. 2012; 24: 991-1001.

    Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87: E1-9.

    Koschatzky S, Gmeiner P. Selective agonists for dopamine/neurotensin receptor heterodimers. ChemMedChem. 2012; 7: 509-14.

    Constitutive dimerization of the G-protein coupled receptor, neurotensin receptor 1, 12.

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