期刊
PHARMACOLOGY & THERAPEUTICS
卷 187, 期 -, 页码 114-132出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2018.02.008
关键词
Relaxin; insulin-like peptides; RXFP1; LGR; GPCR
资金
- National Health and Medical Research Council of Australia project [628427, 1043750, 1122170]
- Victorian Government Operational Infrastructure Support Program
- Australian Research Council [LE120100022]
- NHMRC Research Fellowship [1042650]
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Norwegian Research Council BIOTEK project SALMOSTERILE [221648]
- Australian Research Council [LE120100022] Funding Source: Australian Research Council
- National Health and Medical Research Council of Australia [1122170] Funding Source: NHMRC
The peptide relaxin was first identified as an important circulating hormone during pregnancy over 90 years ago. Research over many years defined the numerous biological roles that relaxin plays throughout pregnancy in many mammalian species. These important biological actions have led to the testing of relaxin as a therapeutic agent for a number of indications. The discovery of the relaxin receptor, RXFP1, in 2002 facilitated the better understanding of the cellular targets of relaxin, its mechanism of action and enabled the development of relaxin mimetics and screening for small molecule agonists. Additionally, the rapid expansion of the genome databases and bioinformatics tools has significantly advanced our understanding of the evolution of the relaxin/RXFP1 signaling system. It is now clear that the relaxin-RXFP1 signaling axis is far more ancient than previously appreciated with important roles for invertebrate relaxin-like peptides in reproductive and non-reproductive functions. This review summarizes these advances as well as developments in drug targeting of RXFP1. Hence the complex mode of activation of RXFP1 is discussed as is the discovery and development of a peptide mimetic and small molecule agonist. Detailed signaling studies are summarized which highlight the cell specific signaling of a peptide mimetic and biased signaling of a small molecule agonist. These studies highlight the complexities of targeting peptide GPCRs such as RXFP1. (C) 2018 Elsevier Inc. All rights reserved.
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