GLP1R

Official Full Name

glucagon like peptide 1 receptor

Organism

Homo sapiens

Gene ID

2740

Background

This gene encodes a 7-transmembrane protein that functions as a receptor for glucagon-like peptide 1 (GLP-1) hormone, which stimulates glucose-induced insulin secretion. This receptor, which functions at the cell surface, becomes internalized in response to GLP-1 and GLP-1 analogs, and it plays an important role in the signaling cascades leading to insulin secretion. It also displays neuroprotective effects in animal models. Polymorphisms in this gene are associated with diabetes. The protein is an important drug target for the treatment of type 2 diabetes and stroke. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2016]

Synonyms

GLP-1; GLP-1R; GLP-1-R

Cat.No.	Product Name	Price
CSC-DC006329	Panoply™ Human GLP1R Knockdown Stable Cell Line	Inquiry
CSC-SC006329	Panoply™ Human GLP1R Over-expressing Stable Cell Line	Inquiry
CSC-SC006329-1	Human GLP1R Stable Cell Line-CHO	Inquiry
CSC-RG01846	Human GLP1R Stable Cell Line - HEK293	Inquiry
CSC-RG0487	Human GLP1R Stable Cell Line-CHO-K1	Inquiry

Cat.No.	Product Name	Price
AD00179Z	Human GLP1R adenoviral particles	Inquiry
AD06820Z	Human GLP1R adenoviral particles	Inquiry
LV13678L	human GLP1R (NM_002062) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
VLP-N-00008	Human GLP1R Virus-Like Particles	Inquiry

Cat.No.	Product Name	Price
SHH087347	shRNA set against Human GLP1R(NM_002062.3)	Inquiry
SHH087383	shRNA set against Rat Glp1r(NM_012728.1)	Inquiry
SHH301902	shRNA set against Human GLP1R (NM_002062.3)	Inquiry
SHH301906	shRNA set against Mouse GLP1R (NM_021332.2)	Inquiry
SHW002813	shRNA set against Chicken GLP1R (NM_001135551)	Inquiry
SHH087365	shRNA set against Mouse Glp1r(NM_021332.2)	Inquiry
SHH301910	shRNA set against Rat GLP1R (NM_012728.1)	Inquiry

Cat.No.	Product Name	Price
OE-PNDC000105	Human GLP1R Nanodisc	Inquiry
OE-PNDC000818	Human GLP1R Nanodisc	Inquiry

Cat.No.	Product Name	Price
CDCR255129	Mouse Glp1r ORF Clone(NM_021332.2)	Inquiry
CDFR010541	Rat Glp1r cDNA Clone(NM_012728.1)	Inquiry
MiUTR1H-04070	GLP1R miRNA 3'UTR clone	Inquiry
MiUTR1M-05080	GLP1R miRNA 3'UTR clone	Inquiry
MiUTR1R-02135	GLP1R miRNA 3'UTR clone	Inquiry
CDCB164288	Chicken GLP1R ORF Clone (NM_001135551)	Inquiry
CDCB183894	Rabbit GLP1R ORF clone (XM_002714692.2)	Inquiry
CDCR377588	Rat Glp1r ORF Clone(NM_012728.1)	Inquiry

Detailed Information

The GLP-1R is a transmembrane-spanning protein belonging to the family B/secretin GPCRs, mediating the effects of endogenous GLP-1 peptides, as well as the endogenous peptide oxyntomodulin and exogenous peptide exendin-4. Characteristic of family B GPCRs, the GLP-1R possesses a long extracellular N-terminus with an α-helical region, five β-strands forming two antiparallel β-sheets and six conserved cysteine residues that form disulfide interactions. These features allow the receptor to adopt the classic ‘Sushi domain’ or ‘short consensus repeat’, which aids N-terminal stability and confers a high level of structural homology within the N-terminal regions of family B GPCRs. The large extracellular N-terminus has an important role in peptide binding, supported by GLP-1 binding the isolated N-terminus of the GLP-1R and crystal structures of the isolated GLP-1R N-terminus in complex with GLP-1 and exendin peptides. Specifically, the C-terminus of the peptide interacts with the N-terminus of the receptor, which is proposed to be responsible for ligand recognition and specificity, while the N-terminus of the peptide is suggested to associate with the core of the receptor, and is proposed to have a major influence in signaling specificity and transmission.

The expression of the GLP-1R

Expression of the GLP-1R has been demonstrated in pancreatic islets of rodents and humans, which is consistent with the large amount of data demonstrating GLP-1 potentiation of glucose stimulated insulin secretion (GSIS). Insulin-secreting beta cells comprise 65–80% of the cells of the pancreatic islet with glucagon-secreting α-cells comprising 15–20% and somatostatin secreting δ-cells 3–10%. Based on the central location of mRNA and autoradiographic GLP-1 signal and further confirmed with immunofluorescence, GLP-1R is expressed on beta cells, and this expression is consistent with the expression on insulinomas from rodents and humans. Apart from the expression on islet beta cells, GLP-1R is present on the ductal exocrine cells, an observation that may be important in relation to pancreatitis associated with the use of GLP-1 mimetics.

GLP-1R signalling and regulation

The physiological changes observed with increases in GLP-1, including increases in insulin secretion and β-cell mass, which rely on signalling via GLP-1R-mediated intracellular pathways. The GLP-1R is a pleiotropically coupled receptor, with evidence for signalling by multiple G-protein-coupled pathways. However, the GLP-1R is most well documented for its role in Gαs coupling, favoring production of cAMP through increasing enzymatic activity of adenylate cyclase. Moreover, GLP-1R activation induces membrane depolarization of β-cells through inhibition of K+ channels, allowing voltage-dependent Ca²⁺ channels (VDCCs) to open and acceleration of Ca²⁺ influx to occur, resulting in the exocytosis of insulin from β-cells. Thus, the production of cAMP and influx of Ca²⁺ are vital components in the biosynthesis and secretion of insulin. GLP-1R activity also promotes EGFR (epidermal growth factor receptor) transactivation, PI3K (phosphoinositide 3-kinase) activity, IRS-2 (insulin receptor substrate-2) signalling, and subsequently, ERK1/2 (extracellular-signal regulated kinase 1 and 2) activity, as well as nuclear translocation of PKCζ to mediate β-cell proliferation and differentiation as well as promote insulin gene transcription. Apart from G-protein-coupled pathways, there are recently emerging studies suggesting that GRK (GPCR kinase) and β-arrestin recruitment are involved in optimal GLP-1R function. Clear evidence for this is seen in β-cell knockdown of β-arrestin-1, which leads to attenuated cAMP and consequently diminished insulin secretion.

Figure 1. GLP-1R-mediated signalling in pancreatic β-cells.

GLP-1R activation for the treatment of stroke

GLP-1R is broadly expressed in the adult brain, with its main expression in neurons. Furthermore, adult neural stem cells/progenitors are positive for GLP-1R. Glia cells seem not to express GLP-1R unless following inflammation, in response to stroke or to a mechanical lesion. GLP-1 receptor activation has been reported to be beneficial for behavioral recovery and to improve learning and memory in animal models of neurodegenerative disorders. In addition, GLP-1R activation stimulates brain regeneration in normal rodents as well as in response to neurodegeneration or stroke. Finally, GLP-1R activation promotes synaptic plasticity, neurite outgrow and rearrangement, which are all important factors for stroke recovery. In summary, these data show a potential use of a GLP-1R-mediated therapy to also treat patients in the long-term recovery phase after stroke. In this perspective, experimental evidence is almost entirely lacking and – consequently – future preclinical work is urgently needed. Considering the proliferative action of GLP-1R activation, careful surveillance of any oncogenic or growth-promoting effects of preneoplastic lesions in the regenerating tissue is highly warranted.

References:

Darsalia V, et al. GLP-1R activation for the treatment of stroke: updating and future perspectives. Reviews in Endocrine & Metabolic Disorders, 2014, 15(3):233-42.
Pabreja K, et al. Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation. British Journal of Pharmacology, 2014, 171(5):1114-1128.
Koole C, et al. Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function. Biochemical Society Transactions, 2013, 41(1):172-179.
Baggio L L, Drucker D J. Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. Journal of Clinical Investigation, 2014, 124(10):4223-6.

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