Mechanosensitive gating of Kv channels

Area of Science:

• Biophysics
• Molecular Biology
• Neuroscience

Background:

• K-selective voltage-gated channels (Kv) are crucial for neuronal function.
• Their mechanosensitive (MS) properties are linked to conformational changes within the cell membrane.
• Existing models propose different mechanisms for Kv channel mechanosensitivity.

Purpose of the Study:

• To re-evaluate the prevailing models of Kv channel mechanosensitivity.
• To determine the most accurate biophysical mechanism underlying MS-Kv channel function.
• To assess the physiological implications of different MS-Kv models on neuronal excitability.

Main Methods:

• Analysis of existing experimental data on Kv channel gating and inactivation.
• Comparison of two proposed models: a tension-dependent equilibrium constant (L) model versus a voltage-dependent transition model.
• Computational modeling of neuronal excitability incorporating different MS-Kv channel behaviors.

Main Results:

• The L-based model, attributing mechanosensitivity to a tension-dependent closed-open transition, fails to predict observed Kv channel kinetics and responses.
• Incorporating slow inactivation into existing datasets fully supports a voltage-dependent closed-closed transition model with an invariant L.
• The voltage-dependent model accurately predicts Kv channel densities and is compatible with physiological membrane tension.
• Excitability modeling demonstrates that MS V-dependent transitions yield nuanced mechanical modulation of neuronal firing, unlike the extreme inhibition predicted by the L-based model.

Conclusions:

• The prevailing L-based model for MS-Kv channels is insufficient and inaccurate.
• A voltage-dependent closed-closed transition model provides a more robust explanation for MS-Kv channel behavior.
• This revised understanding of MS-Kv channels has significant implications for their role in tuning pain-related neuronal excitability.