Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms
- New Jersey Medical School, Rutgers University, United States
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
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.
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
-
- 3,795
- views
-
- 444
- downloads
-
- 39
- 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)
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
