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Related Experiment Videos

Screening for AMPA receptor auxiliary subunit specific modulators.

Caleigh M Azumaya1, Emily L Days2, Paige N Vinson2

  • 1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

Plos One
|March 31, 2017
PubMed
Summary

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This summary is machine-generated.

Researchers developed a new screening method to find compounds targeting specific AMPA receptor (AMPAR) auxiliary subunit complexes. This approach identifies novel modulators for potential brain region-selective treatments for neurological and psychiatric disorders.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • AMPA receptors (AMPARs) are crucial for brain function, and their dysfunction is linked to neurological and psychiatric diseases.
  • Targeting specific AMPAR auxiliary subunit complexes offers a strategy for developing brain region-selective treatments with fewer side effects.

Purpose of the Study:

  • To establish a high-throughput screening pipeline for identifying compounds selective for GluA2-CNIH3 and GluA2-stargazin AMPAR complexes.
  • To discover novel negative and positive allosteric modulators (NAMs and PAMs) for these specific AMPAR complexes.

Main Methods:

  • A cell-based assay utilizing voltage-sensitive dyes (VSD) to detect glutamate-gated cation flow.
  • Co-expression of GluA2 with auxiliary subunits (CNIH3, stargazin) in HEK cells.

Related Experiment Videos

  • Validation of initial screening hits using a calcium flux assay.

    • Main Results:

    • A screening pipeline successfully identified compounds selective for GluA2-CNIH3 and GluA2-stargazin complexes.
    • VU0612951 (NAM) and VU0627849 (PAM) were identified as modulators with differential efficacy on stargazin/CNIH3 complexes.
    • VU0539491 demonstrated dual activity, acting as a NAM on GluA2-CNIH3 and a PAM on GluA2-GSG1L complexes.

    Conclusions:

    • The developed screening pipeline effectively identifies selective modulators of AMPAR-auxiliary subunit complexes.
    • These novel compounds, including VU0612951, VU0627849, and VU0539491, provide valuable tools for further research into AMPAR function and therapeutic development.
    • This strategy advances the development of brain region-selective therapeutics by targeting specific AMPAR complexes.