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Intracellular Ca2+ signaling and human disease: the hunt begins with Huntington's
Anurag Varshney1, Barbara E Ehrlich
1Department of Pharmacology and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
Insights
Altered huntingtin protein in Huntington's disease enhances neuronal calcium signaling. This makes neurons hyperresponsive, potentially increasing susceptibility to neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease involves polyglutamine expansion in the huntingtin protein.
- Huntingtin interacts with the inositol trisphosphate receptor (InsP3R) and Htt-associated protein 1A (HAP1A).
Discussion:
- Polyglutamine-expanded huntingtin (Httexp) alters the InsP3R-HAP1A complex.
- This alteration increases InsP3R sensitivity to InsP3.
Key Insights:
- Httexp binding leads to hyperresponsiveness in neurons.
- This heightened neuronal excitability is a potential driver of neurodegeneration in Huntington's disease.
Outlook:
- Understanding this molecular mechanism may reveal new therapeutic targets.
- Further research can explore modulating this signaling pathway to protect neurons.
Abstract:
Huntingtin, a protein altered by polyglutamine expansion in Huntington's disease (Httexp), forms a signaling complex with the InsP3R, an intracellular calcium channel, and Htt-associated protein 1A (HAP1A). The addition of Httexp increases the InsP3R sensitivity to InsP3, which subsequently makes neurons hyperresponsive to stimulation and presumably more prone to neurodegenerative processes.