کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2534922 1559106 2008 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Identification of the domains in RXFP4 (GPCR142) responsible for the high affinity binding and agonistic activity of INSL5 at RXFP4 compared to RXFP3 (GPCR135)
کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
Identification of the domains in RXFP4 (GPCR142) responsible for the high affinity binding and agonistic activity of INSL5 at RXFP4 compared to RXFP3 (GPCR135)
چکیده انگلیسی

Relaxin-3 is a potent agonist for both G-protein coupled receptors (GPCR) RXFP3 (also known as GPCR135) and RXFP4 (also known as GPCR142) while insulin-like peptides 5 (INSL5) is a selective RXFP4 agonist. INSL5 is also a weak (low affinity) RXFP3 antagonist. RXFP3 and RXFP4 share about 50% homology. We have used gain-of-function (RXFP3 → RXFP4) and loss-of-function (RXFP4 → RXFP3) chimeras to identify the domains critical for the binding and activation induced by INSL5. Replacing extracellular loop (EL) 1 or EL3 of RXFP3 with the corresponding domains from RXFP4 does not change the RXFP3 pharmacological profile. Exchanging the N-terminus and EL2 of RXFP3 with these of RXFP4 results in a chimeric receptor (CR5) with a high affinity for INSL5. However, in contrast to native RXFP4, INSL5 does not elicit an agonist response from CR5. Conversely, replacing the N-terminus and EL2 of RXFP4 with counterparts from RXFP3 (CR15) results in a chimeric receptor for which relaxin-3 and INSL5 are high and low affinity agonists, respectively. Further mutagenesis studies indicate that transmembrane (TM) domains 2, 3 and 5 of RXFP4 are critical determinants of functional receptor activation by INSL5. Replacement of TM2, 3, and 5 of RXFP3 with equivalent domains from RXFP4 results in a chimeric receptor that can be activated by INSL5. These results suggest that the N-terminus and EL2 domains of RXFP3 and RXFP4 are involved in ligand binding while TM2, 3, and 5 are critical for receptor activation.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 590, Issues 1–3, 20 August 2008, Pages 43–52
نویسندگان
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