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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^* and P. Michael Conn^*,,,1

^* Divisions of Neuroscience and Reproductive Sciences, Oregon National Primate Research Center and

Departments of Physiology and Pharmacology and

Cell and Developmental Biology, Oregon Health and Science University, Beaverton, Oregon, USA

¹ Correspondence: ONPRC/OHSU, 505 NW 185th Ave., Beaverton, OR 97006, USA. E-mail: connm{at}ohsu.edu

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 K_d 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.—Janovick, J., Brothers, S. P., Knollman, P. E., Conn, P. M. Specializations of a G-protein-coupled receptor that appear to aid with detection of frequency-modulated signals from its ligand.

Key Words: quality control system • pharmacoperone • pharmacological chaperone • protein routing • receptor evolution

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