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Structural basis of neuropeptide Y signaling through Y1 receptor.

ABSTRACT: Neuropeptide Y (NPY) is highly abundant in the brain and involved in various physiological processes related to food intake and anxiety, as well as human diseases such as obesity and cancer. However, the molecular details of the interactions between NPY and its receptors are poorly understood. Here, we report a cryo-electron microscopy structure of the NPY-bound neuropeptide Y1 receptor (Y₁R) in complex with G_i1 protein. The NPY C-terminal segment forming the extended conformation binds deep into the Y₁R transmembrane core, where the amidated C-terminal residue Y36 of NPY is located at the base of the ligand-binding pocket. Furthermore, the helical region and two N-terminal residues of NPY interact with Y₁R extracellular loops, contributing to the high affinity of NPY for Y₁R. The structural analysis of NPY-bound Y₁R and mutagenesis studies provide molecular insights into the activation mechanism of Y₁R upon NPY binding.

SUBMITTER: Park C

PROVIDER: S-EPMC8844075 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Structural basis of neuropeptide Y signaling through Y1 receptor.

Park Chaehee C Kim Jinuk J Ko Seung-Bum SB Choi Yeol Kyo YK Jeong Hyeongseop H Woo Hyeonuk H Kang Hyunook H Bang Injin I Kim Sang Ah SA Yoon Tae-Young TY Seok Chaok C Im Wonpil W Choi Hee-Jung HJ

Nature communications 20220214 1

Neuropeptide Y (NPY) is highly abundant in the brain and involved in various physiological processes related to food intake and anxiety, as well as human diseases such as obesity and cancer. However, the molecular details of the interactions between NPY and its receptors are poorly understood. Here, we report a cryo-electron microscopy structure of the NPY-bound neuropeptide Y1 receptor (Y<sub>1</sub>R) in complex with G<sub>i1</sub> protein. The NPY C-terminal segment forming the extended confo ...[more]

PMID: 35165283

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Project description:ObjectivesLoss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D.MethodsThe gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese (db/db) T2D mouse models were assessed.ResultsIn this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice.ConclusionsOur results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D.

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Structural basis of neuropeptide Y signaling through Y1 receptor.

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Structural basis of neuropeptide Y signaling through Y1 receptor.

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