Specializations of a G-protein-coupled receptor that appear to aid with detection of frequency-modulated signals from its ligand

Jo Ann Janovick, Shaun P. Brothers, Paul E. Knollman, P. Michael Conn

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)384-392
Number of pages9
JournalFASEB Journal
Volume21
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

Keywords

  • Pharmacological chaperone
  • Pharmacoperone
  • Protein routing
  • Quality control system
  • Receptor evolution

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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