Biased agonists at the human Y 1 receptor lead to prolonged membrane residency and extended receptor G protein interacti
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Biased agonists at the human Y1 receptor lead to prolonged membrane residency and extended receptor G protein interaction Anette Kaiser1 · Lizzy Wanka1 · Isabelle Ziffert1 · Annette G. Beck‑Sickinger1 Received: 23 September 2019 / Revised: 2 December 2019 / Accepted: 18 December 2019 © Springer Nature Switzerland AG 2020
Abstract Functionally selective ligands to address specific cellular responses downstream of G protein-coupled receptors (GPCR) open up new possibilities for therapeutics. We designed and characterized novel subtype- and pathway-selective ligands. Substitution of position Q 34 of neuropeptide Y to glycine ( G34-NPY) results in unprecedented selectivity over all other YR subtypes. Moreover, this ligand displays a significant bias towards activation of the Gi/o pathway over recruitment of arrestin-3. Notably, no bias is observed for an established Y 1R versus Y 2R selective ligand carrying a proline at position 34 (F7,P34-NPY). Next, we investigated the spatio-temporal signaling at the Y1R and demonstrated that G protein-biased ligands promote a prolonged localization at the cell membrane, which leads to enhanced G protein signaling, while endosomal receptors do not contribute to cAMP signaling. Thus, spatial components are critical for the signaling of the Y1R that can be modulated by tailored ligands and represent a novel mode for biased pathways. Graphic abstract
Keywords GPCR · NPY · Signaling bias · Arrestin · G Protein
Introduction
Anette Kaiser and Lizzy Wanka contributed equally. * Annette G. Beck‑Sickinger abeck‑sickinger@uni‑leipzig.de 1
Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany
Within the past years our knowledge on receptor activation and signaling has rapidly increased. To date, we know that the classical two-state receptor model is insufficient to describe the mechanism of receptor activation [1]. A multistate model has evolved, which supports the existence of different inactive and active states of a receptor. Ligands as well as effector proteins may shift the conformational equilibria by conformational selection and/or induced fit [2, 3]. Thus,
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a specific ligand can favour distinct signaling pathways. In a clinical context, this may be used to optimize efficacy or reduce side effects of new pharmaceuticals. One of the first examples was TRV027, an arrestin-biased agonist of the angiotensin II type 1 receptor considered for the treatment of high blood pressure in patients with acute heart failure [4, 5]. While this particular compound did not reach the market [6, 7], this concept has gained a lot of interest and may be applied to any GPCR. However, functionally selective ligands have been reported so far for only a small subset of potentially clinically interesting receptors. Moreover, in multi-ligand/multi-receptor systems, the requirements for subtype specificity add another layer of complexity to the design of
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