期刊
PHARMACOLOGICAL REVIEWS
卷 67, 期 2, 页码 389-440出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/pr.114.009472
关键词
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资金
- National Health and Medical Research Council (NHMRC) of Australia [1047633]
- RD Wright Career Development Fellowship [1061687]
- NHMRC [628427, 1043750, 519461, 1055134]
- Victorian Government Operational Infrastructure Support Program
- NHMRC Research Fellowship
- BAS Medical Inc. [89874634, 89844575]
- Zentrales Innovationsprogramm Mittelstand [KF2181501AJ9, KF2318301]
- Wellcome Trust [099156/Z/12/Z]
Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate ligands for the relaxin family peptide (RXFP) receptors 1-4, respectively. RXFP1 activates pleiotropic signaling pathways including the signalosome protein complex that facilitates high-sensitivity signaling; coupling to G alpha(s), G alpha(i), and G alpha(o) proteins; interaction with glucocorticoid receptors; and the formation of hetero-oligomers with distinctive pharmacological properties. In addition to relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related protein 8 and by small-molecular-weight agonists, such as ML290 [2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl) benzamide], that act allosterically. RXFP2 activates only the G alpha(s)- and G alpha(o)-coupled pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3 is a target for the treatment of depression, anxiety, and autism. A variety of peptide agonists, antagonists, biased agonists, and an allosteric modulator target RXFP3. Both RXFP3 and the related RXFP4 couple to G alpha(i)/G alpha(o) proteins. INSL5 has the properties of an incretin; it is secreted from the gut and is orexigenic. The expression of RXFP4 in gut, adipose tissue, and beta-islets together with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a metabolic role. This review focuses on the many advances in our understanding of RXFP receptors in the last 5 years, their signal transduction mechanisms, the development of novel compounds that target RXFP1-4, the challenges facing the field, and current prospects for new therapeutics.
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