N-terminal alterations turn the gut hormone GLP-2 into an antagonist with gradual loss of GLP-2 receptor selectivity towards more GLP-1 receptor interaction
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N-terminal alterations turn the gut hormone GLP-2 into an antagonist with gradual loss of GLP-2 receptor selectivity towards more GLP-1 receptor interaction. / Gabe, Maria Buur Nordskov; Gasbjerg, Laerke Smidt; Gadgaard, Sarina; Lindquist, Peter; Holst, Jens Juul; Rosenkilde, Mette Marie.
I: British Journal of Pharmacology, Bind 179, Nr. 18, 2022, s. 4473-4485.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - N-terminal alterations turn the gut hormone GLP-2 into an antagonist with gradual loss of GLP-2 receptor selectivity towards more GLP-1 receptor interaction
AU - Gabe, Maria Buur Nordskov
AU - Gasbjerg, Laerke Smidt
AU - Gadgaard, Sarina
AU - Lindquist, Peter
AU - Holst, Jens Juul
AU - Rosenkilde, Mette Marie
N1 - © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2022
Y1 - 2022
N2 - BACKGROUND AND PURPOSE: To fully elucidate the regulatory role of the GLP-2 system in the gut and the bones, potent and selective GLP-2 receptor (GLP-2R) antagonists are needed. Searching for antagonist activity, we performed systematic N-terminal truncations of human GLP-2(1-33).EXPERIMENTAL APPROACH: COS-7 cells were transfected with the human GLP-2R and assessed for cAMP accumulation or competition binding using 125 I-GLP-2(1-33)[M10Y]. To examine selectivity, COS-7 cells expressing human GLP-1 or GIP receptors were assessed for cAMP accumulation.KEY RESULTS: Affinity of the N-terminally truncated GLP-2 peptides for the GLP-2 receptor decreased with reduced N-terminal peptide length (Ki 6.5-871 nM), while increasing antagonism appeared with inhibitory potencies (IC50 ) values from 79 to 204 nM for truncation up to GLP-2(4-33) and then declined. In contrast, truncation-dependent increases in intrinsic activity were observed from an Emax of only 20% for GLP-(2-33) up to 46% for GLP-2(6-33) at 1 μM, followed by a decline. GLP-2(9-33) had the highest intrinsic efficacy (Emax 65%) and no antagonistic properties. Moreover, with truncations up to GLP-2(8-33), a gradual loss in selectivity for the GLP-2 receptor appeared with increasing GLP-1 receptor (GLP-1R) inhibition (up to 73% at 1 μM). Lipidation of the peptides improved antagonism (IC50 down to 7.9 nM) for both the GLP-2 and the GLP-1R.CONCLUSION AND IMPLICATIONS: The N-terminus of GLP-2 is crucial for GLP-2R activity and selectivity. Our observations form the basis for the development of tool compounds for further characterization of the GLP-2 system.
AB - BACKGROUND AND PURPOSE: To fully elucidate the regulatory role of the GLP-2 system in the gut and the bones, potent and selective GLP-2 receptor (GLP-2R) antagonists are needed. Searching for antagonist activity, we performed systematic N-terminal truncations of human GLP-2(1-33).EXPERIMENTAL APPROACH: COS-7 cells were transfected with the human GLP-2R and assessed for cAMP accumulation or competition binding using 125 I-GLP-2(1-33)[M10Y]. To examine selectivity, COS-7 cells expressing human GLP-1 or GIP receptors were assessed for cAMP accumulation.KEY RESULTS: Affinity of the N-terminally truncated GLP-2 peptides for the GLP-2 receptor decreased with reduced N-terminal peptide length (Ki 6.5-871 nM), while increasing antagonism appeared with inhibitory potencies (IC50 ) values from 79 to 204 nM for truncation up to GLP-2(4-33) and then declined. In contrast, truncation-dependent increases in intrinsic activity were observed from an Emax of only 20% for GLP-(2-33) up to 46% for GLP-2(6-33) at 1 μM, followed by a decline. GLP-2(9-33) had the highest intrinsic efficacy (Emax 65%) and no antagonistic properties. Moreover, with truncations up to GLP-2(8-33), a gradual loss in selectivity for the GLP-2 receptor appeared with increasing GLP-1 receptor (GLP-1R) inhibition (up to 73% at 1 μM). Lipidation of the peptides improved antagonism (IC50 down to 7.9 nM) for both the GLP-2 and the GLP-1R.CONCLUSION AND IMPLICATIONS: The N-terminus of GLP-2 is crucial for GLP-2R activity and selectivity. Our observations form the basis for the development of tool compounds for further characterization of the GLP-2 system.
U2 - 10.1111/bph.15866
DO - 10.1111/bph.15866
M3 - Journal article
C2 - 35523760
VL - 179
SP - 4473
EP - 4485
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 18
ER -
ID: 310852547