Faculty Opinions recommendation of Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.

Several G-protein-coupled receptors contain cysteine residues in the C-terminal tail that may modulate receptor function. In this work we analysed the substitution of Cys438 by alanine in the glucagon-like peptide-1 (GLP-1) receptor (GLPR), which led to a threefold decrease in cAMP production, although endocytosis and cellular redistribution of GLP-1 receptor agonist-induced processes were unaffected. Additionally, cysteine residues in the C-terminal tail of several G-protein-coupled receptors were found to act as substrates for palmitoylation, which might modify the access of protein kinases to this region. His-tagged GLP-1 receptors incorporated 3H-palmitate. Nevertheless, substitution of Cys438 prevented the incorporation of palmitate. Accordingly, we also investigated the effect of substitution of the consensus sequence by protein kinase C (PKC) Ser431/432 in both wild-type and Ala438 GLP-1 receptors. Substitution of Ser431/432 by alanine did not modify the ability of wild-type receptors to stimulate adenylate cyclase or endocytosis and recycling processes. By contrast, the substitution of Ser431/432 by alanine in the receptor containing Ala438 increased the ability to stimulate adenylate cyclase. All types of receptors were mainly internalised through coated pits. Thus, cysteine 438 in the cytoplasmic tail of the GLP-1 receptor would regulate its interaction with G-proteins and the stimulation of adenylyl cyclase. Palmitoylation of this residue might control the access of PKC to Ser431/432.

Download Full-text

Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1218051109 ◽

2012 ◽

Vol 109 (49) ◽

pp. 19988-19993 ◽

Cited By ~ 34

Author(s):

A. Kirkpatrick ◽

J. Heo ◽

R. Abrol ◽

W. A. Goddard

Keyword(s):

G Protein ◽

G Protein Coupled Receptor ◽

Class B ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled

Download Full-text

Investigation of ECD conformational transition mechanism of GLP-1R by molecular dynamics simulations and Markov state model

Physical Chemistry Chemical Physics ◽

10.1039/c9cp00080a ◽

2019 ◽

Vol 21 (16) ◽

pp. 8470-8481 ◽

Cited By ~ 5

Author(s):

Jintu Zhang ◽

Qifeng Bai ◽

Horacio Pérez-Sánchez ◽

Shuxia Shang ◽

Xiaoli An ◽

...

Keyword(s):

Conformational Transition ◽

G Protein Coupled Receptors ◽

Markov State Model ◽

Markov State ◽

Transition Mechanism ◽

Class B ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Dynamics Simulations ◽

G Protein Coupled

As a member of the class B G protein-coupled receptors (GPCRs), the glucagon-like peptide-1 (GLP-1) can regulate the blood glucose level by binding to the glucagon-like peptide-1 receptor (GLP-1R).

Download Full-text

Purification of family B G protein-coupled receptors using nanodiscs: Application to human glucagon-like peptide-1 receptor

PLoS ONE ◽

10.1371/journal.pone.0179568 ◽

2017 ◽

Vol 12 (6) ◽

pp. e0179568 ◽

Cited By ~ 14

Author(s):

Yingying Cai ◽

Yuting Liu ◽

Kelly J. Culhane ◽

Brian T. DeVree ◽

Yang Yang ◽

...

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled

Download Full-text

Design and preparation of the class B G protein‐coupled receptors GLP‐1R and GCGR for 19 F‐NMR studies in solution

FEBS Journal ◽

10.1111/febs.15686 ◽

2020 ◽

Author(s):

Huixia Wang ◽

Wanhui Hu ◽

Dongsheng Liu ◽

Kurt Wüthrich

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Nmr Studies ◽

Class B ◽

G Protein Coupled ◽

19 F Nmr

Download Full-text

Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00010.2019 ◽

2019 ◽

Vol 316 (5) ◽

pp. G574-G584 ◽

Cited By ~ 9

Author(s):

Charlotte Bayer Christiansen ◽

Samuel Addison Jack Trammell ◽

Nicolai Jacob Wewer Albrechtsen ◽

Kristina Schoonjans ◽

Reidar Albrechtsen ◽

...

Keyword(s):

Bile Acids ◽

G Protein ◽

Peptide Yy ◽

Whole Body ◽

Rat Colon ◽

G Protein Coupled Receptor ◽

L Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled

A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.5- and 2.9-fold, respectively. Furthermore, we find that responses depend on BA absorption followed by basolateral activation of the BA-receptor Takeda-G protein-coupled-receptor 5. Surprisingly, the apical sodium-dependent BA transporter, which serves to absorb conjugated BAs, was not required for colonic conjugated BA absorption or conjugated BA-induced peptide secretion. In conclusion, we demonstrate that BAs represent a major physiological stimulus for colonic L-cell secretion.NEW & NOTEWORTHY By the use of isolated perfused rodent colon preparations we show that bile acids are potent and direct promoters of colonic glucagon-like-peptide 1 and peptide-YY secretion. The study provides convincing evidence that basolateral Takeda-G protein-coupled-receptor 5 activation is mediating the effects of bile acids in the colon and thus add to the existing literature described for L cells in the ileum.

Download Full-text