{beta}Adrenoceptor-mediated regulation of glucose uptake in skeletal muscle-ligand-directed signalling or a reflection of system complexity?

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Abstract

The capacity of G protein-coupled receptors (GPCRs) to activate multiple G protein isoforms and additional effectors such as beta-arrestins has become a well-established paradigm and provides the basis for developing drugs that preferentially activate beneficial signalling pathways. There are many published examples of ligand-directed signalling, and recent studies have provided direct evidence that different agonists stabilise distinct GPCR conformations. This field is rapidly evolving, but a key question is whether signalling bias observed in heterologous cell expression systems can be translated to physiological systems of therapeutic relevance. The paper by Ngala et al. in this issue of the journal addresses the capacity of agonists acting at the beta2-adrenoceptor to engender signalling bias in relation to glucose uptake in isolated skeletal muscle, an area of considerable potential interest in targeting insulin-independent pathways for the treatment of type 2 diabetes. The authors show that clenbuterol and BRL37344 have opposite effects on glucose uptake, despite both having agonist actions at beta2-adrenoceptors. This study underlines some of the obstacles associated with studies in a complex physiological system but nonetheless highlights the need to consider signalling bias in the relevant target tissue when developing novel drugs.
Original languageEnglish
Pages (from-to)757 - 760
Number of pages4
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume386
Issue number9
DOIs
Publication statusPublished - 2013

Cite this

@article{d762f17136db4d858117a43225946602,
title = "{beta}Adrenoceptor-mediated regulation of glucose uptake in skeletal muscle-ligand-directed signalling or a reflection of system complexity?",
abstract = "The capacity of G protein-coupled receptors (GPCRs) to activate multiple G protein isoforms and additional effectors such as beta-arrestins has become a well-established paradigm and provides the basis for developing drugs that preferentially activate beneficial signalling pathways. There are many published examples of ligand-directed signalling, and recent studies have provided direct evidence that different agonists stabilise distinct GPCR conformations. This field is rapidly evolving, but a key question is whether signalling bias observed in heterologous cell expression systems can be translated to physiological systems of therapeutic relevance. The paper by Ngala et al. in this issue of the journal addresses the capacity of agonists acting at the beta2-adrenoceptor to engender signalling bias in relation to glucose uptake in isolated skeletal muscle, an area of considerable potential interest in targeting insulin-independent pathways for the treatment of type 2 diabetes. The authors show that clenbuterol and BRL37344 have opposite effects on glucose uptake, despite both having agonist actions at beta2-adrenoceptors. This study underlines some of the obstacles associated with studies in a complex physiological system but nonetheless highlights the need to consider signalling bias in the relevant target tissue when developing novel drugs.",
author = "Evans, {Bronwyn Anne} and Hutchinson, {Dana Sabine} and Summers, {Roger James}",
year = "2013",
doi = "10.1007/s00210-013-0879-7",
language = "English",
volume = "386",
pages = "757 -- 760",
journal = "Naunyn-Schmiedeberg's Archives of Pharmacology",
issn = "0028-1298",
publisher = "Springer-Verlag London Ltd.",
number = "9",

}

TY - JOUR

T1 - {beta}Adrenoceptor-mediated regulation of glucose uptake in skeletal muscle-ligand-directed signalling or a reflection of system complexity?

AU - Evans, Bronwyn Anne

AU - Hutchinson, Dana Sabine

AU - Summers, Roger James

PY - 2013

Y1 - 2013

N2 - The capacity of G protein-coupled receptors (GPCRs) to activate multiple G protein isoforms and additional effectors such as beta-arrestins has become a well-established paradigm and provides the basis for developing drugs that preferentially activate beneficial signalling pathways. There are many published examples of ligand-directed signalling, and recent studies have provided direct evidence that different agonists stabilise distinct GPCR conformations. This field is rapidly evolving, but a key question is whether signalling bias observed in heterologous cell expression systems can be translated to physiological systems of therapeutic relevance. The paper by Ngala et al. in this issue of the journal addresses the capacity of agonists acting at the beta2-adrenoceptor to engender signalling bias in relation to glucose uptake in isolated skeletal muscle, an area of considerable potential interest in targeting insulin-independent pathways for the treatment of type 2 diabetes. The authors show that clenbuterol and BRL37344 have opposite effects on glucose uptake, despite both having agonist actions at beta2-adrenoceptors. This study underlines some of the obstacles associated with studies in a complex physiological system but nonetheless highlights the need to consider signalling bias in the relevant target tissue when developing novel drugs.

AB - The capacity of G protein-coupled receptors (GPCRs) to activate multiple G protein isoforms and additional effectors such as beta-arrestins has become a well-established paradigm and provides the basis for developing drugs that preferentially activate beneficial signalling pathways. There are many published examples of ligand-directed signalling, and recent studies have provided direct evidence that different agonists stabilise distinct GPCR conformations. This field is rapidly evolving, but a key question is whether signalling bias observed in heterologous cell expression systems can be translated to physiological systems of therapeutic relevance. The paper by Ngala et al. in this issue of the journal addresses the capacity of agonists acting at the beta2-adrenoceptor to engender signalling bias in relation to glucose uptake in isolated skeletal muscle, an area of considerable potential interest in targeting insulin-independent pathways for the treatment of type 2 diabetes. The authors show that clenbuterol and BRL37344 have opposite effects on glucose uptake, despite both having agonist actions at beta2-adrenoceptors. This study underlines some of the obstacles associated with studies in a complex physiological system but nonetheless highlights the need to consider signalling bias in the relevant target tissue when developing novel drugs.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=23657252

U2 - 10.1007/s00210-013-0879-7

DO - 10.1007/s00210-013-0879-7

M3 - Letter

VL - 386

SP - 757

EP - 760

JO - Naunyn-Schmiedeberg's Archives of Pharmacology

JF - Naunyn-Schmiedeberg's Archives of Pharmacology

SN - 0028-1298

IS - 9

ER -