Molecular Characterisation of Small Molecule Agonists Effect on the Human Glucagon Like Peptide-1 Receptor Internalisation

Thompson, Aiysha; Stephens, Jeffrey W.; Bain, Stephen C.; Kanamarlapudi, Venkateswarlu

doi:10.1371/journal.pone.0154229

Cited by 21 publications

(37 citation statements)

References 49 publications

(104 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structural relevance of various domains of GLP-1R has been elucidated by numerous studies (Thompson and Kanamarlapudi 2013, 2015a. The pathway(s) required for agonist-induced GLP-1R internalization has also been elucidated (Thompson and Kanamarlapudi 2015b). GLP-1 analogues are currently used to treat type 2 diabetes to promote normoglycemia in patients (Thompson and Kanamarlapudi 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Endocytosis in this manner can lead to fission of caveolae enriched vesicles and then fusion with caveosomes (Thompson and Kanamarlapudi 2013). The Gaq pathway has recently been shown to be important for the agonist-induced GLP-1R internalization (Thompson and Kanamarlapudi 2015b). GLP-1R resensitization is not well studied but it has been shown that GLP-1R-mediated calcium signalling resensitizes within 1 h after agonist removal (Graaf et al 2016).…”

Section: The Ecls Of Gpcrs Have Been Demonstratedmentioning

confidence: 99%

“…Compounds 2 and B induced cAMP production in human GLP-1R expressing cells but caused no intracellular Ca2+ accumulation, ERK phosphorylation, or receptor internalization (Thompson et al 2016). The K334A mutation (which affects Gas coupling) of GLP-1R inhibited both GLP-1 and compounds 2 and B induced cAMP production; this indicates that GLP-1 and both compounds 2 and B induce similar conformational changes for G-protein activation (Thompson et al 2016). A recent study showed that compounds 2 and B bind and covalently modify Cys347 in ICL3 of GLP-1R (Nolte et al 2014).…”

mentioning

confidence: 92%

“…One study showed that compound B almost normalized insulin secretion in human islets isolated from a donor with type 2 diabetes (Thompson and Kanamarlapudi 2013). Compounds 2 and B bind to a distinct site from the orthosteric binding site as GLP-1 antagonists Ex(9-39) and JANT4 as well as the V36A mutation failed to inhibit cAMP production upon compound 2 or B administration (Thompson et al 2016). Compounds 2 and B induced cAMP production in human GLP-1R expressing cells but caused no intracellular Ca2+ accumulation, ERK phosphorylation, or receptor internalization (Thompson et al 2016).…”

mentioning

confidence: 99%

“…Compounds 2 and B bind to a distinct site from the orthosteric binding site as GLP-1 antagonists Ex(9-39) and JANT4 as well as the V36A mutation failed to inhibit cAMP production upon compound 2 or B administration (Thompson et al 2016). Compounds 2 and B induced cAMP production in human GLP-1R expressing cells but caused no intracellular Ca2+ accumulation, ERK phosphorylation, or receptor internalization (Thompson et al 2016). The K334A mutation (which affects Gas coupling) of GLP-1R inhibited both GLP-1 and compounds 2 and B induced cAMP production; this indicates that GLP-1 and both compounds 2 and B induce similar conformational changes for G-protein activation (Thompson et al 2016).…”

mentioning

confidence: 99%

See 4 more Smart Citations

GLP-1r

Reed¹,

Kanamarlapudi²

2016

Encyclopedia of Signaling Molecules

Self Cite

View full text Add to dashboard Cite

Historical Background In the 1960s, it was shown that orally administered glucose induces a much stronger insulin response than that induced by intravenously administered glucose, despite the similar resulting plasma glucose levels; this was termed the "incretin effect" (Creutzfeldt 2005; Graaf et al. 2016). Gastric inhibitory peptide (GIP) was the first incretin hormone to be discovered in 1975, which is produced by K cells of the small intestine (Creutzfeldt 2005). It was then observed in 1981 that antibodies against GIP did not abolish the incretin effect which led to the discovery of glucagon-like peptide-1 (GLP-1) in the translational products of mRNAs isolated from pancreatic islets of anglerfish (Shields et al. 1981; Graaf et al. 2016). Subsequently, it was shown that hamster and human preproglucagon cDNAs encode GLP-1 and 2, but only GLP-1 possessed incretin activity (Graaf et al. 2016). After the discovery of GLP-1, research was undertaken to identify its receptor. The GLP-1 receptor (GLP-1R) was first cloned from a cDNA library derived from rat pancreatic islets in 1992, and in 1993 the human receptor was successfully cloned (Donnelly 2012; Graaf et al. 2016).

show abstract

Section: Discussionmentioning

confidence: 99%

Section: The Ecls Of Gpcrs Have Been Demonstratedmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

GLP-1r

Reed¹,

Kanamarlapudi²

2016

Encyclopedia of Signaling Molecules

Self Cite

View full text Add to dashboard Cite

show abstract

GLP-1r

Reed¹,

Kanamarlapudi²

2018

Encyclopedia of Signaling Molecules

View full text Add to dashboard Cite

Gaba

2018

Encyclopedia of Signaling Molecules

View full text Add to dashboard Cite

G alpha o 1893G regulators of the Gao protein may provide a cellspecific mechanism for Gao-regulated signaling pathways. PTX catalyzes the ADP-ribosylation of the a subunits of the Go, Gi, and Gt proteins at the C-terminal cysteine residue (À4 position). This prevents the G protein from interacting with GPCRs on the cell membrane, thus interfering with intracellular signaling. 1896 G alpha o G alpha o 1897 G cyclase, guanylate cyclase, Rap1 GTPaseactivating protein (Rap1GAP), axin, and pins. Compartmentalization of these signaling molecules in membrane rafts may ensure specificity and fidelity in Gao signaling. Go is the most abundant G protein in the central nervous system, where it comprises about 1% of membrane proteins in the mammalian brain. Go regulates neuronal development, memory, visual reception, olfactory reception, and taste reception. It is also localized in heart tissue and implicated in heart contractility. Its expression is regulated during the development of the brain and heart. Somatic mutations in the GNAO1 gene induce human cancers by rendering Gao constitutively activated. Heterozygous mutations in the GNAO1 gene cause epileptic encephalopathy by destabilizing Gao. Gao-deficient mice have several neurological deficits, including tremors, seizures, hyperalgesia, motor control impairment, and olfactory impairment. Muscarinic regulation of heart rate and heart rate variability is also impaired in Gao-deficient mice. Drosophila melanogaster mutants with loss of function of Gao show impaired morphogenesis of the heart and epithelial polarity of cardiac cells and abnormal sleep. Gao-deficient C. elegans has phenotypes including neuronal migration defects, hyperactive locomotion, and egg laying.

show abstract

Molecular Characterisation of Small Molecule Agonists Effect on the Human Glucagon Like Peptide-1 Receptor Internalisation

Cited by 21 publications

References 49 publications

GLP-1r

GLP-1r

GLP-1r

Gaba

Contact Info

Product

Resources

About