TY - JOUR
T1 - A Novel Antagonist Peptide Reveals a Physiological Role of Insulin-Like Peptide 5 in Control of Colorectal Function
AU - Pustovit, Ruslan V.
AU - Zhang, Xiaozhou
AU - Liew, Jamie J.M.
AU - Praveen, Praveen
AU - Liu, Mengjie
AU - Koo, Ada
AU - Oparija-Rogenmozere, Lalita
AU - Ou, Qinghao
AU - Kocan, Martina
AU - Nie, Shuai
AU - Bathgate, Ross A.D.
AU - Furness, John B.
AU - Hossain, Mohammed Akhter
N1 - Publisher Copyright:
©
PY - 2021/10/8
Y1 - 2021/10/8
N2 - Insulin-like peptide 5 (INSL5), the natural ligand for the relaxin family peptide receptor 4 (RXFP4), is a gut hormone that is exclusively produced by colonic L-cells. We have recently developed an analogue of INSL5, INSL5-A13, that acts as an RXFP4 agonist in vitro and stimulates colorectal propulsion in wild-type mice but not in RXFP4-knockout mice. These results suggest that INSL5 may have a physiological role in the control of colorectal motility. To investigate this possibility, in this study we designed and developed a novel INSL5 analogue, INSL5-A13NR. This compound is a potent antagonist, without significant agonist activity, in two in vitro assays. We report here for the first time that this novel antagonist peptide blocks agonist-induced increase in colon motility in mice that express RXFP4. Our data also show that colorectal propulsion induced by intracolonic administration of bacterial products (short-chain fatty acids, SCFAs) is antagonized by INSL5-A13NR. Therefore, INSL5-A13NR is an important research tool and potential drug lead for the treatment of colon motility disorders, such as bacterial diarrheas.
AB - Insulin-like peptide 5 (INSL5), the natural ligand for the relaxin family peptide receptor 4 (RXFP4), is a gut hormone that is exclusively produced by colonic L-cells. We have recently developed an analogue of INSL5, INSL5-A13, that acts as an RXFP4 agonist in vitro and stimulates colorectal propulsion in wild-type mice but not in RXFP4-knockout mice. These results suggest that INSL5 may have a physiological role in the control of colorectal motility. To investigate this possibility, in this study we designed and developed a novel INSL5 analogue, INSL5-A13NR. This compound is a potent antagonist, without significant agonist activity, in two in vitro assays. We report here for the first time that this novel antagonist peptide blocks agonist-induced increase in colon motility in mice that express RXFP4. Our data also show that colorectal propulsion induced by intracolonic administration of bacterial products (short-chain fatty acids, SCFAs) is antagonized by INSL5-A13NR. Therefore, INSL5-A13NR is an important research tool and potential drug lead for the treatment of colon motility disorders, such as bacterial diarrheas.
KW - colon motility
KW - GPCR
KW - INSL5
KW - insulin-like peptide 5
KW - relaxin family peptide receptor 4
KW - RXFP4
UR - https://www.scopus.com/pages/publications/85114702834
U2 - 10.1021/acsptsci.1c00171
DO - 10.1021/acsptsci.1c00171
M3 - Article
AN - SCOPUS:85114702834
SN - 2575-9108
VL - 4
SP - 1665
EP - 1674
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 5
ER -