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Molecular determinants of ASIC1 modulation by divalent cations
Yi Liu1, Jichun Ma2, Renee L DesJarlais2
1Neuroscience Discovery, Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, USA.
Scientific Reports
|January 28, 2024
Summary
Divalent cations modulate acid-sensing ion channels (ASICs) by binding to an acidic pocket site. This binding is crucial for regulating ASIC1a channel gating, offering insights into channel modulation mechanisms.
Area of Science:
- Neuroscience
- Ion Channel Physiology
- Molecular Biology
Background:
- Acid-sensing ion channels (ASICs) are proton-gated cation channels vital for nervous system functions.
- ASIC gating is influenced by divalent cations and small molecules, but the mechanisms remain unclear.
- Previous work identified small molecules modulating ASIC1a gating similarly to divalent cations.
Purpose of the Study:
- To investigate the interaction between divalent cations and small molecules on ASIC1a.
- To elucidate the molecular basis of divalent cation modulation on ASIC1a channel gating.
Main Methods:
- Utilized mutational analysis of ASIC1a.
- Examined the effects of divalent cations and identified small molecules on ASIC1a gating.
- Investigated the binding site within the acidic pocket.
Main Results:
- Divalent cation binding to an acidic pocket site is a key determinant of ASIC1a gating modulation.
- The identified small molecules and divalent cations interact at this site.
- Mutational studies confirmed the role of the acidic pocket in modulation.
Conclusions:
- The acidic pocket is a critical site for divalent cation-mediated gating modulation of ASIC1a.
- Understanding this interaction provides a molecular basis for ASIC channel regulation.
- This research offers potential targets for therapeutic interventions involving ASICs.
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