PMID- 27243589
OWN - NLM
STAT- MEDLINE
DCOM- 20180405
LR  - 20190424
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 6
DP  - 2016 May 31
TI  - Regulating the effects of GPR21, a novel target for type 2 diabetes.
PG  - 27002
LID - 10.1038/srep27002 [doi]
LID - 27002
AB  - Type 2 diabetes is a chronic metabolic disorder primarily caused by insulin 
      resistance to which obesity is a major contributor. Expression levels of an 
      orphan G protein-coupled receptor (GPCR), GPR21, demonstrated a trend towards a 
      significant increase in the epididymal fat pads of wild type high fat high sugar 
      (HFHS)-fed mice. To gain further insight into the potential role this novel 
      target may play in the development of obesity-associated type 2 diabetes, the 
      signalling capabilities of the receptor were investigated. Overexpression studies 
      in HEK293T cells revealed GPR21 to be a constitutively active receptor, which 
      couples to Galphaq type G proteins leading to the activation of mitogen activated 
      protein kinases (MAPKs). Overexpression of GPR21 in vitro also markedly 
      attenuated insulin signalling. Interestingly, the effect of GPR21 on the MAPKs 
      and insulin signalling was reduced in the presence of serum, inferring the 
      possibility of a native inhibitory ligand. Homology modelling and ligand docking 
      studies led to the identification of a novel compound that inhibited GPR21 
      activity. Its effects offer potential as an anti-diabetic pharmacological 
      strategy as it was found to counteract the influence of GPR21 on the insulin 
      signalling pathway.
FAU - Leonard, Siobhan
AU  - Leonard S
AD  - Department of Biology, National University of Ireland Maynooth, Maynooth, Co. 
      Kildare, Ireland.
FAU - Kinsella, Gemma K
AU  - Kinsella GK
AD  - Department of Biology, National University of Ireland Maynooth, Maynooth, Co. 
      Kildare, Ireland.
FAU - Benetti, Elisa
AU  - Benetti E
AD  - Department of Drug Science and Technology, University of Turin, Turin, Italy.
FAU - Findlay, John B C
AU  - Findlay JBC
AD  - Department of Biology, National University of Ireland Maynooth, Maynooth, Co. 
      Kildare, Ireland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160531
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Estrenes)
RN  - 0 (GPR21 protein, human)
RN  - 0 (GPR21 protein, mouse)
RN  - 0 (Pyrrolidinones)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 112648-68-7 
      (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione)
RN  - 57-50-1 (Sucrose)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.24 (MAPK1 protein, human)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 3.6.5.1 (G protein alpha 16)
RN  - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gq-G11)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Type 2/*drug therapy/etiology/genetics/pathology
MH  - Diet, High-Fat/adverse effects
MH  - Estrenes/pharmacology
MH  - GTP-Binding Protein alpha Subunits, Gq-G11/*genetics/metabolism
MH  - Gene Expression Regulation
MH  - HEK293 Cells
MH  - Humans
MH  - Insulin Resistance
MH  - MAP Kinase Kinase 4/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitogen-Activated Protein Kinase 1/genetics/metabolism
MH  - Mitogen-Activated Protein Kinase 3/genetics/metabolism
MH  - Protein Kinase C/antagonists & inhibitors/genetics/metabolism
MH  - Pyrrolidinones/pharmacology
MH  - Receptors, G-Protein-Coupled/antagonists & inhibitors/*genetics/metabolism
MH  - Signal Transduction
MH  - Sucrose/adverse effects
MH  - p38 Mitogen-Activated Protein Kinases/*genetics/metabolism
PMC - PMC4886680
EDAT- 2016/06/01 06:00
MHDA- 2018/04/06 06:00
PMCR- 2016/05/31
CRDT- 2016/06/01 06:00
PHST- 2016/02/17 00:00 [received]
PHST- 2016/05/12 00:00 [accepted]
PHST- 2016/06/01 06:00 [entrez]
PHST- 2016/06/01 06:00 [pubmed]
PHST- 2018/04/06 06:00 [medline]
PHST- 2016/05/31 00:00 [pmc-release]
AID - srep27002 [pii]
AID - 10.1038/srep27002 [doi]
PST - epublish
SO  - Sci Rep. 2016 May 31;6:27002. doi: 10.1038/srep27002.