title: Specializations of a G-protein-coupled receptor that appear to aid with detection of frequency-modulated signals from its ligand.
abstract: The primate GnRH receptor (GnRHR) is a GPCR (G-protein-coupled receptor) that transduces both amplitude- and frequency-modulated signals; each modality conveys information that regulates primate reproduction. Slower GnRH pulses favor release (and higher circulating levels) of pituitary FSH, while faster pulses favor LH release. We used radioligand binding and inositol phosphate production (a measure of G-protein coupling) in association with mutational analysis to identify the impact of evolved sequence specializations that regulate receptor concentration at the plasma membrane and Kd in primate GnRHRs. Our results show that mutations appear to provide a mechanism that allows independent adjustment of response sensitivity and squelching (suppression) of low-level signals (noise), both desirable features for recognition of frequency-modulated signals. We identify specific amino acid residues that appear to be involved in these processes. This investigation occurred in light of recent observations that restriction of GnRHR plasma membrane expression developed under strong convergent pressure and concurrently with the complex pattern of cyclicity associated with primate reproduction. The findings present an evolved means for increased effectiveness of detection of a frequency-modulated signal and provide a strategy to identify similar mechanisms in other receptors.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Janovick
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Brothers
authors.forename: Paul E
authors.initials: PE
authors.lastname: Knollman
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002064:Buserelin / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D003545:Cysteine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011323:Primates; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011966:Receptors, LHRH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014162:Transfection
chemical_list: D007295:Inositol Phosphates; D050505:Mutant Proteins; D043562:Receptors, G-Protein-Coupled; D011966:Receptors, LHRH; D008239:Lysine; D003545:Cysteine; D002064:Buserelin