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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Changes to gonadotropin-releasing hormone (GnRH) receptor extracellular loops differentially affect GnRH analog binding and activation: Evidence for distinct ligand-stabilized receptor conformations
Endocrinology, Volume 149, No. 6, Year 2008
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Description
GnRH and its structural variants bind to GnRH receptors from different species with different affinities and specificities. By investigating chimeric receptors that combine regions of mammalian and nonmammalian GnRH receptors, a greater understanding of how different domains influence ligand binding and receptor activation can be achieved. Using human-catfish and human-chicken chimeric receptors, we demonstrate the importance of extracellular loop conformation for ligand binding and agonist potency, providing further evidence for GnRH and GnRH II stabilization of distinct active receptor conformations. We demonstrate examples of GnRH receptor gain-of-function mutations that apparently improve agonist potency independently of affinity, implicating a role for extracellular loops in stabilizing the inactive receptor conformation. We also show that entire extracellular loop substitution can overcome the detrimental effects of localized mutations, thereby demonstrating the importance of considering the conformation of entire domains when drawing conclusions from point-mutation studies. Finally, we present evidence implicating the configuration of extracellular loops 2 and 3 in combination differentiating GnRH analog binding modes. Because there are two endogenous forms of GnRHligand but only one functional form of full-length GnRH receptor in humans, understanding how GnRH and GnRH II can elicit distinct functional effects through the same receptor is likely to provide important insights into how these ligands can have differential effects in both physiological and pathological situations. Copyright © 2008 by The Endocrine Society.
Authors & Co-Authors
Pfleger, Kevin D.G.
United Kingdom, Edinburgh
Mrc Human Reproductive Sciences Unit
Australia, Perth
Queen Elizabeth Ii Medical Centre Trust
Australia, Perth
The Harry Perkins Institute of Medical Research
Pawson, Adam J.
United Kingdom, Edinburgh
Mrc Human Reproductive Sciences Unit
Millar, Robert P.
United Kingdom, Edinburgh
Mrc Human Reproductive Sciences Unit
Statistics
Citations: 20
Authors: 3
Affiliations: 3
Identifiers
Doi:
10.1210/en.2008-0002
ISSN:
00137227
Research Areas
Cancer