Biased Signaling Favoring Gi over β-Arrestin Promoted by an Apelin Fragment Lacking the C-terminal Phenylalanine

Ceraudo, Emilie; Galanth, Cécile; Carpentier, Éric Le; Banegas, Inmaculada; Schönegge, Anne–Marie; Alvear-Perez, Rodrigo; Iturrioz, Xavier; Bouvier, Michel; Llorens-Cortes, Catherine

doi:10.1074/jbc.m113.541698

Cited by 60 publications

(111 citation statements)

References 65 publications

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“…Apelin-17 lacking this phenylalanine (apelin-K16P) can no longer induce APJ internalization or lower blood pressure while it retains binding and signaling properties (inhibition of forskolin-induced cAMP production) . Attesting these results, Ceraudo et al recently demonstrated that apelin-K16P was still a bioactive peptide (Ceraudo et al, 2014). This point will be discussed later in the review.…”

Section: Introductionmentioning

confidence: 91%

Apelin receptors: From signaling to antidiabetic strategy

Chaves-Almagro

Castan-Laurell

Dray

et al. 2015

European Journal of Pharmacology

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Section: Introductionmentioning

confidence: 91%

Apelin receptors: From signaling to antidiabetic strategy

Chaves-Almagro

Castan-Laurell

Dray

et al. 2015

European Journal of Pharmacology

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“…APJ has been shown to dimerize with the AT1 receptor to inhibit the effects of angiotensin II signaling in a model of atherosclerosis (21), with the bradykinin 1 receptor to mediate apelin-13-dependent PKC activation and endothelial NOS (eNOS) phosphorylation (22), and with neurotensin receptor 1 to mediate apelin-13-and neurotensindependent phosphorylation of ERK1/2 and cell proliferation (23). Additionally, Ceraudo et al (24) reported that apelin-17 signals in a ␤-arrestin-dependent and G protein-dependent manner, whereas apelin-17 missing the C-terminal phenylalanine signals only through G proteins.…”

Section: Discussionmentioning

confidence: 99%

Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling

Galon-Tilleman

Yang

Bednarek³

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinApelin-36 was discovered as the endogenous ligand for the previously orphan receptor APJ. Apelin-36 has been linked to two major types of biological activities: cardiovascular (stimulation of cardiac contractility and suppression of blood pressure) and metabolic (improving glucose homeostasis and lowering body weight). It has been assumed that both of these activities are modulated through APJ. Here, we demonstrate that the metabolic activity of apelin-36 can be separated from canonical APJ activation. We developed a series of apelin-36 variants in which evolutionarily conserved residues were mutated, and evaluated their ability to modulate glucose homeostasis and body weight in chronic mouse models. We found that apelin-36(L28A) retains full metabolic activity, but is 100-fold impaired in its ability to activate APJ. In contrast to its full metabolic activity, apelin-36(L28A) lost the ability to suppress blood pressure in spontaneously hypertensive rats (SHR). We took advantage of these findings to develop a longer-acting variant of apelin-36 that could modulate glucose homeostasis without impacting blood pressure (or activating APJ). Apelin-36-[L28C(30kDa-PEG)] is 10,000-fold less potent than apelin-36 at activating the APJ receptor but retains its ability to significantly lower blood glucose and improve glucose tolerance in diet-induced obese mice. Apelin-36-[L28C(30kDa-PEG)] provides a starting point for the development of diabetes therapeutics that are devoid of the blood pressure effects associated with canonical APJ activation.The apelin gene encodes a pre-pro-protein that is processed into a number of regulatory hormones. The best characterized of these peptide hormones are apelin-13, apelin-17, and apelin-36 (1). The 13 C-terminal amino acids of these peptides (comprising apelin-13) are shared, with apelin-17 extending an additional 4 amino acids from the N terminus, and apelin-36 extending a further 19 amino acids beyond the N terminus of apelin-17 (see Table 1). Apelin was discovered as an endogenous agonist of the G protein-coupled receptor APJ (2). Specifically, apelin-36 was purified from bovine stomach tissue extract based on its ability to stimulate signaling through APJ.Through a combination of pharmacological and genetic approaches, apelin has been linked to two major types of biological activities: cardiovascular (stimulation of cardiac contractility and suppression of blood pressure) and metabolic (improving glucose homeostasis and lowering body weight) (3, 4). Both of these activities have been assumed to be mediated solely through APJ, but there is substantial evidence to suggest that APJ may have apelin-independent activities (5, 6). Here, we provide evidence that this ligand-receptor promiscuity goes in both directions, and that apelin may have APJ-independent activities as well. Specifically, we demonstrate that the metabolic activity of apelin-36 can be dissociated from canonical APJ signaling. ResultsTo evaluate the chronic metabolic activity of apelin peptid...

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“…The challenge of hNPS-(1-10) induced an increase in luciferase activity but with significantly less potency as compared with wild type NPS, having an EC 50 value of 64.26 Ϯ 2.38 M. Our data indicate that there are interesting differences in agonist activity for hNPS-(1-10) between G␣ q and G␣ s coupling. Therefore, we next performed a quantitative analysis of hNPS-(1-10) bias based on functional parameters using an operational model as described previously (25,27,28). As shown in Table 1, hNPS-(1-10) activation of NPSR revealed a significant bias (Ͼ80-fold) for G␣ q activation over G␣ s .…”

Section: Hnps-(1-10) Exhibits Preferential Activity In G␣ Q -Coupled mentioning

confidence: 99%

Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

Yuan

Lü

et al. 2016

Journal of Biological Chemistry

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Human neuropeptide S (NPS) and its cognate receptor regulate important biological functions in the brain and have emerged as a future therapeutic target for treatment of a variety of neurological and psychiatric diseases. The human NPS (hNPS) receptor has been shown to dually couple to G␣ s -and G␣ q -dependent signaling pathways. The human NPS analog hNPS-(1-10), lacking 10 residues from the C terminus, has been shown to stimulate Ca 2؉ mobilization in a manner comparable with full-length hNPS in vitro but seems to fail to induce biological activity in vivo. Here, results derived from a number of cellbased functional assays, including intracellular cAMP-response element (CRE)-driven luciferase activity, Ca 2؉ mobilization, and ERK1/2 phosphorylation, show that hNPS-(1-10) preferentially activates G␣ q -dependent Ca 2؉ mobilization while exhibiting less activity in triggering G␣ s -dependent CRE-driven luciferase activity. We further demonstrate that both G␣ q -and G␣ s -coupled signaling pathways contribute to full-length hNPS-mediated activation of ERK1/2, whereas hNPS-(1-10)-promoted ERK1/2 activation is completely inhibited by the G␣ q inhibitor UBO-QIC but not by the PKA inhibitor H89. Moreover, the results of Ala-scanning mutagenesis of hNPS-(1-13) indicated that residues Lys 11 and Lys 12 are structurally crucial for the hNPS receptor to couple to G␣ s -dependent signaling. In conclusion, our findings demonstrate that hNPS-(1-10) is a biased agonist favoring G␣ q -dependent signaling. It may represent a valuable chemical probe for further investigation of the therapeutic potential of human NPS receptor-directed signaling in vivo.

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Biased Signaling Favoring Gi over β-Arrestin Promoted by an Apelin Fragment Lacking the C-terminal Phenylalanine

Cited by 60 publications

References 65 publications

Apelin receptors: From signaling to antidiabetic strategy

Apelin receptors: From signaling to antidiabetic strategy

Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling

Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

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