Three-amino acid motifs of urocortin II and III determine their CRF receptor subtype selectivity

Neuropharmacology
O JahnJ Spiess

Abstract

Corticotropin-releasing factor (CRF) and the CRF-like peptide urocortin I (UcnI) exert their activity through two different CRF receptors, CRF1 and CRF2. Recently, UcnII and UcnIII have been discovered as potential endogenous agonists selective for CRF2 known to be involved in brain functions such as learning and anxiety, as well as in cardiovascular functions. A structure-affinity relationship study using chimeric peptides was designed to characterize mouse UcnII (mUcnII) and mUcnIII further and to investigate the structural basis of their receptor subtype selectivity. In the framework of this study, mUcnII (IC50 = 4.4 nM) but not mUcnIII was identified as high-affinity ligand for the rat CRF binding protein. Such affinity had previously not been observed for the human version of this protein. On the basis of secondary structure predictions, it was hypothesized that the amino acid motifs Pro-Ile-Gly of mUcnII and Pro-Thr-Asn of mUcnIII decrease alpha-helicity and thereby impair binding to CRF1. In support of this hypothesis, binding affinity to CRF1 of the chimeric peptides [Pro11Ile12Gly13]h/rCRF, [Pro11Thr12Asn13]h/rCRF, and the corresponding rUcnI analogs was found to be decreased by three orders of magnitude, whereas bindi...Continue Reading

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Citations

May 19, 2005·Neuroscience and Biobehavioral Reviews·Martin E KeckMarianne B Müller
Nov 15, 2008·The Journal of Endocrinology·Audrey F SeasholtzRobert C Thompson
Aug 2, 2005·FEBS Letters·Christos TsatsanisAndrew N Margioris
Oct 24, 2009·Biochemical and Biophysical Research Communications·Chie TanakaAkio Inui
Nov 7, 2006·Frontiers in Neuroendocrinology·Eva M Fekete, Eric P Zorrilla
Sep 3, 2011·British Journal of Pharmacology·Dimitris K Grammatopoulos
Aug 16, 2005·Neuroscience and Biobehavioral Reviews·Cedomir TodorovicJoachim Spiess
Apr 12, 2016·Journal of Cellular Physiology·Justyna M WierzbickaAndrzej T Slominski
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Aug 16, 2018·Physiological Reviews·Jan M Deussing, Alon Chen
Oct 15, 2005·American Journal of Physiology. Gastrointestinal and Liver Physiology·József CzimmerYvette Taché
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Jun 26, 2021·Frontiers in Neuroendocrinology·Chayarndorn PhumsatitpongSuzanne M Moenter

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