New screening process could lead to next-generation therapeutics for a
broad spectrum of diseases
High-throughput screening provides insight into functional role of key G protein-coupled receptor (GPCR) rhodopsin (Rh)

Date:
November 16, 2021
Source:
University of California - Irvine
Summary:
Researchers have developed a high-throughput screen methodology to
identify compounds affect a key G protein coupled receptor (GPCR)
rhodopsin (Rh). GPCRs mediate many important physiological functions
and are considered to be one of the most effective therapeutic
targets for a broad spectrum of diseases, ranging from diabetes
to immune system disorders.



FULL STORY ==========================================================================
A new study led by University of California, Irvine researchers developed
a high-throughput screen methodology to identify compounds affect a key
G protein coupled receptor (GPCR) rhodopsin (Rh). GPCRs mediate many
important physiological functions and are considered to be one of the
most effective therapeutic targets for a broad spectrum of diseases,
ranging from diabetes to immune system disorders.


==========================================================================
The study, titled "Identification of small molecule allosteric modulators
that act as enhancers/disrupters of rhodopsin oligomerization," was
published in the Journal of Biological Chemistry,and provides a monitoring
tool for future investigation of the Rh signaling cascade. It also reveals
the discovery of new allosteric modulators of Rh dimerization that can
also alter the physiology of rod photoreceptors in the eye. The team
identified lead compounds that demonstrated allosteric modulation of
rod light response kinetics or reduction of rod sensitivity. The next
step will be to use medicinal chemistry to improve the pharmacological properties of the lead compounds.

"Our employed methodology will open new avenues for study, tremendously benefitting the discipline of pharmacology by improving understanding
of the role of GPCR dimerization," said Krzysztof Palczewski, PhD,
Donald Bren Professor of Ophthalmology in the UCI School of Medicine and corresponding author. "This approach will also be tested in other GPCR
systems such as opioid, adrenergic receptors and others, paving the way to discovery of other more selective modulations of GPCR signaling. These
advanced insights result in the identification and production of next-generation medications." Understanding the functional role of
GPCRs, and identifying compounds that either enhance or disrupt the dimerization of the GPCR rhodopsin (Rh), could provide the key to unlock
the full potential of these most effective therapeutic targets. Recent
studies have shown that many GPCRs exist as dimers and oligomers, and that their organization is an essential requirement for proper operation. The functional role of the dimerization of Rh is currently unknown due to
a lack of precise structural information.

Other members of the research team included Tamar Getter, UCI biochemistry
of vision post-doctoral fellow; Frans Vinberg, PhD, ophthalmology/visual sciences assistant professor; and Albert Kemp, biomedical engineering
student, both from the University of Utah, Salt Lake City.

This work was funded by grants R01EY014800, P30EY026651, and R24EY027283
from the National Institutes of Health, as well as from Research to
Prevent Blindness, the Department of Ophthalmology at UCI, and the
Department of Ophthalmology & Visual Sciences at University of Utah.

========================================================================== Story Source: Materials provided by
University_of_California_-_Irvine. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Tamar Getter, Albert Kemp, Frans Vinberg, Krzysztof Palczewski.

Identification of small molecule allosteric modulators that act
as enhancers/disrupters of rhodopsin oligomerization. Journal of
Biological Chemistry, 2021; 101401 DOI: 10.1016/j.jbc.2021.101401 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211116175028.htm

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