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Opening the shaker K+ channel with hanatoxin
Mirela Milescu1, Hwa C Lee, Chan Hyung Bae
1Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of General Physiology
|January 30, 2013
Summary
Tarantula toxins interacting with Shaker Kv channels can either inhibit or promote channel opening. Fine structural details at the toxin-channel interface determine the toxin
Area of Science:
- Molecular and Cellular Biology
- Neuroscience
- Biophysics
Background:
- Voltage-activated ion channels are crucial for electrical signaling, with their gating modulated by protein toxins.
- Tarantula toxins, like hanatoxin, often target the voltage-sensing domains (S1-S4) of these channels.
- Hanatoxin inhibits Kv2.1 channels by stabilizing a closed state, but its effect on Shaker Kv channels is different.
Purpose of the Study:
- To investigate the interaction of hanatoxin with the extensively studied Shaker Kv channel.
- To elucidate how hanatoxin binding affects the gating properties of Shaker Kv channels.
- To determine the structural basis for differential effects of tarantula toxins on Kv channels.
Main Methods:
- Biophysical characterization of hanatoxin interaction with wild-type and mutant Shaker Kv channels.
- Utilizing previously characterized Shaker Kv channel mutants to assess toxin effects.
- Employing chimeras between Kv2.1 and Shaker Kv channels to study toxin-channel interface.
- Testing the effects of the related tarantula toxin GxTx-1E.
Main Results:
- Hanatoxin shifts the conductance-voltage relation of Shaker Kv channels to negative voltages, facilitating opening.
- Mutations in the S3b helix of the S1-S4 domain enhance hanatoxin affinity and gating shifts.
- Hanatoxin stabilizes an activated conformation of voltage sensors and promotes channel opening.
- Toxin actions depend on specific structural details of the toxin-channel interface, not just binding site.
Conclusions:
- Hanatoxin acts as an opener for Shaker Kv channels, unlike its inhibitory effect on Kv2.1 channels.
- The S3b helix is critical for high-affinity hanatoxin binding and modulation of Shaker Kv channel gating.
- Structural nuances of the toxin-channel interface dictate whether tarantula toxins inhibit or activate Kv channels.
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