1. Neuroscience
  2. Structural Biology and Molecular Biophysics
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Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms

  1. Siyuan Zhao  Is a corresponding author
  2. Yevgen Yudin
  3. Tibor Rohacs  Is a corresponding author
  1. New Jersey Medical School, Rutgers University, United States
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Cite this article as: eLife 2020;9:e55634 doi: 10.7554/eLife.55634

Abstract

Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca2+ permeable non-selective cation channel activated by heat and chemical agonists such as pregnenolone sulfate and CIM0216. TRPM3 mutations in humans were recently reported to be associated with intellectual disability and epilepsy; the functional effects of those mutations however were not reported. Here we show that both disease-associated mutations in the human TRPM3 render the channel overactive, but likely via different mechanisms. The Val to Met substitution in the S4-S5 loop induced a larger increase in basal activity and agonist sensitivity at room temperature than the Pro to Gln substitution in the extracellular segment of S6. In contrast, heat activation was increased more by the S6 mutant than by the S4-S5 segment mutant. Both mutants were inhibited by the TRPM3 antagonist primidone, suggesting a potential therapeutic intervention to treat this disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Siyuan Zhao

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States
    For correspondence
    sz404@gsbs.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Yevgen Yudin

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Tibor Rohacs

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States
    For correspondence
    rohacsti@njms.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3580-2575

Funding

National Institute of Neurological Disorders and Stroke (NS055159)

  • Tibor Rohacs

National Institute of General Medical Sciences (GM093290)

  • Tibor Rohacs

National Institute of General Medical Sciences (GM131048)

  • Tibor Rohacs

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) of Rutgers University, protocol number 17024.

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Publication history

  1. Received: January 30, 2020
  2. Accepted: April 28, 2020
  3. Accepted Manuscript published: April 28, 2020 (version 1)
  4. Version of Record published: May 28, 2020 (version 2)

Copyright

© 2020, Zhao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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