GLP1R

Official Full Name

glucagon like peptide 1 receptor

Organism

Homo sapiens

GeneID

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;

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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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