High-Throughput Screening Identifies a Rhodopsin Dimer Enhancer Candidate, GPCRs Studied

Article: High-throughput screening provides insight into functional role of key G protein-coupled receptor (GPCR) rhodopsin (Rh)
Source: University of California, Irvine, Medicine
Published: November 16, 2021

Effect of compound #1, a rhodopsin dimer enhancer candidate, on
rod photoreceptor light responses, as measured in mouse retina cells

The transduction of light in the eye's rod photoreceptors relies on G protein-coupled receptors (GPCR) called rhodopsins (Rh), which are the visual pigments in rod photoreceptors. Researchers at UC Irvine sought to study rhodopsin oligomerization, or self-aggregation, and its effect on the rhodopsin G protein-coupled signaling cascade. They performed high-throughput screening on a diverse library of 50,000 small molecules, including a novel assay to detect rhodopsin dimerization. This screening method identified nine small molecules that either disrupted or enhanced rhodopsin dimer contacts in vitro. One of the compounds (hit compound #7) "significantly slowed down the light response kinetics of intact rods," while another compound (hit compound #1) "cause a significant reduction in light sensitivity." Subsequent free-cell binding analysis showed spectra profiles that are consistent with all nine compounds being allosteric modulators. The authors report "the discovery of new allosteric modulators of rhodopsin dimerization that can also alter rod photoreceptor physiology" and new tools for studying the rhodopsin signaling cascade. Because G protein-coupled receptors (including opioid and adrenergic receptors) mediate a variety of physiological functions, studying these receptors can add to knowledge about how they serve as therapeutic targets for a wide range of diseases. They state that next steps include applying medicinal chemistry to improve the pharmacological properties of the identified compounds.

My rating of this study: ⭐⭐ 

Getter T, Kemp A, Vinberg F, et al. "Identification of small-molecule allosteric modulators that act as enhancers/disrupters of rhodopsin oligomerization." Journal of Biological Chemistry.  297(6):101401. December 2021. https://doi.org/10.1016/j.jbc.2021.101401