1. Neuroscience
  2. Structural Biology and Molecular Biophysics

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
https://doi.org/10.7554/eLife.55634
Share this article
Cite this article
  1. Siyuan Zhao
  2. Yevgen Yudin
  3. Tibor Rohacs
(2020)
Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms
eLife 9:e55634.
https://doi.org/10.7554/eLife.55634
  2. Download BibTeX
  3. Download .RIS

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.

Reviewing Editor

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

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.

Version 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.

Metrics

  • 3,490
    views
  • 409
    downloads
  • 29
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Siyuan Zhao
  2. Yevgen Yudin
  3. Tibor Rohacs
(2020)
Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms
eLife 9:e55634.
https://doi.org/10.7554/eLife.55634

Share this article

https://doi.org/10.7554/eLife.55634

Categories and tags

Further reading

    1. Neuroscience

    Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy

    Evelien Van Hoeymissen, Katharina Held ... Joris Vriens
    Short Report Updated

    Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, two de novo heterozygous mutations in the gene encoding TRPM3, a calcium permeable ion channel, were identified as the cause of DEE in eight probands, but the functional consequences of the mutations remained elusive. Here we demonstrate that both mutations (V990M and P1090Q) have distinct effects on TRPM3 gating, including increased basal activity, higher sensitivity to stimulation by the endogenous neurosteroid pregnenolone sulfate (PS) and heat, and altered response to ligand modulation. Most strikingly, the V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward cation currents via the voltage sensor domain in response to PS stimulation. Taken together, these data indicate that the two DEE mutations in TRPM3 result in a profound gain of channel function, which may lie at the basis of epileptic activity and neurodevelopmental symptoms in the patients.

    1. Neuroscience

    Multi-day neuron tracking in high-density electrophysiology recordings using earth mover’s distance

    Augustine Xiaoran Yuan, Jennifer Colonell ... Timothy D Harris
    Tools and Resources

    Accurate tracking of the same neurons across multiple days is crucial for studying changes in neuronal activity during learning and adaptation. Advances in high-density extracellular electrophysiology recording probes, such as Neuropixels, provide a promising avenue to accomplish this goal. Identifying the same neurons in multiple recordings is, however, complicated by non-rigid movement of the tissue relative to the recording sites (drift) and loss of signal from some neurons. Here, we propose a neuron tracking method that can identify the same cells independent of firing statistics, that are used by most existing methods. Our method is based on between-day non-rigid alignment of spike-sorted clusters. We verified the same cell identity in mice using measured visual receptive fields. This method succeeds on datasets separated from 1 to 47 days, with an 84% average recovery rate.

    1. Neuroscience

    Decision Making: Unraveling the enigmatic role of the subthalamic nucleus

    Qianli Yang
    Insight

    Subpopulations of neurons in the subthalamic nucleus have distinct activity patterns that relate to the three hypotheses of the Drift Diffusion Model.