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Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

Atanes, Patricio; Ruz-Maldonado, Inmaculada; Hawkes, Ross; Liu, Bo; Zhao, Min; Huang, Guo Cai; Al-Amily, Israa Mohammed LU ; Salehi, Albert LU ; Amisten, Stefan LU and Persaud, Shanta J. (2018) In Cellular and Molecular Life Sciences
Abstract

Introduction: Islets synthesise and secrete numerous peptides, some of which are known to be important regulators of islet function and glucose homeostasis. In this study, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets and carried out in vitro islet hormone secretion studies to provide functional confirmation for the species-specific role of peptide YY (PYY) in mouse islets. Materials and methods: GPCR peptide ligand mRNAs in human and mouse islets were quantified by quantitative real-time PCR relative to the reference genes ACTB, GAPDH, PPIA, TBP and TFRC. The pathways connecting GPCR peptide ligands with their receptors were identified by manual searches... (More)

Introduction: Islets synthesise and secrete numerous peptides, some of which are known to be important regulators of islet function and glucose homeostasis. In this study, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets and carried out in vitro islet hormone secretion studies to provide functional confirmation for the species-specific role of peptide YY (PYY) in mouse islets. Materials and methods: GPCR peptide ligand mRNAs in human and mouse islets were quantified by quantitative real-time PCR relative to the reference genes ACTB, GAPDH, PPIA, TBP and TFRC. The pathways connecting GPCR peptide ligands with their receptors were identified by manual searches in the PubMed, IUPHAR and Ingenuity databases. Distribution of PYY protein in mouse and human islets was determined by immunohistochemistry. Insulin, glucagon and somatostatin secretion from islets was measured by radioimmunoassay. Results: We have quantified GPCR peptide ligand mRNA expression in human and mouse islets and created specific signalomes mapping the pathways by which islet peptide ligands regulate human and mouse GPCR signalling. We also identified species-specific islet expression of several GPCR ligands. In particular, PYY mRNA levels were ~ 40,000-fold higher in mouse than human islets, suggesting a more important role of locally secreted Pyy in mouse islets. This was confirmed by IHC and functional experiments measuring insulin, glucagon and somatostatin secretion. Discussion: The detailed human and mouse islet GPCR peptide ligand atlases will allow accurate translation of mouse islet functional studies for the identification of GPCR/peptide signalling pathways relevant for human physiology, which may lead to novel treatment modalities of diabetes and metabolic disease.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
GPCRs, Islets of Langerhans, Peptide ligands, PYY, Type 2 diabetes
in
Cellular and Molecular Life Sciences
pages
12 pages
publisher
Birkhaüser
external identifiers
  • scopus:85042132335
ISSN
1420-682X
DOI
10.1007/s00018-018-2778-z
language
English
LU publication?
yes
id
c590d71b-1fec-4434-b69a-b6ee52073f5f
date added to LUP
2018-03-06 08:36:49
date last changed
2018-05-29 12:18:51
@article{c590d71b-1fec-4434-b69a-b6ee52073f5f,
  abstract     = {<p>Introduction: Islets synthesise and secrete numerous peptides, some of which are known to be important regulators of islet function and glucose homeostasis. In this study, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets and carried out in vitro islet hormone secretion studies to provide functional confirmation for the species-specific role of peptide YY (PYY) in mouse islets. Materials and methods: GPCR peptide ligand mRNAs in human and mouse islets were quantified by quantitative real-time PCR relative to the reference genes ACTB, GAPDH, PPIA, TBP and TFRC. The pathways connecting GPCR peptide ligands with their receptors were identified by manual searches in the PubMed, IUPHAR and Ingenuity databases. Distribution of PYY protein in mouse and human islets was determined by immunohistochemistry. Insulin, glucagon and somatostatin secretion from islets was measured by radioimmunoassay. Results: We have quantified GPCR peptide ligand mRNA expression in human and mouse islets and created specific signalomes mapping the pathways by which islet peptide ligands regulate human and mouse GPCR signalling. We also identified species-specific islet expression of several GPCR ligands. In particular, PYY mRNA levels were ~ 40,000-fold higher in mouse than human islets, suggesting a more important role of locally secreted Pyy in mouse islets. This was confirmed by IHC and functional experiments measuring insulin, glucagon and somatostatin secretion. Discussion: The detailed human and mouse islet GPCR peptide ligand atlases will allow accurate translation of mouse islet functional studies for the identification of GPCR/peptide signalling pathways relevant for human physiology, which may lead to novel treatment modalities of diabetes and metabolic disease.</p>},
  author       = {Atanes, Patricio and Ruz-Maldonado, Inmaculada and Hawkes, Ross and Liu, Bo and Zhao, Min and Huang, Guo Cai and Al-Amily, Israa Mohammed and Salehi, Albert and Amisten, Stefan and Persaud, Shanta J.},
  issn         = {1420-682X},
  keyword      = {GPCRs,Islets of Langerhans,Peptide ligands,PYY,Type 2 diabetes},
  language     = {eng},
  month        = {02},
  pages        = {12},
  publisher    = {Birkhaüser},
  series       = {Cellular and Molecular Life Sciences},
  title        = {Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets},
  url          = {http://dx.doi.org/10.1007/s00018-018-2778-z},
  year         = {2018},
}