Role of putative voltage-sensor countercharge D4 in regulating gating properties of CaV1.2 and CaV1.3 calcium channels

CHANNELS, 2018 · DOI: https://doi.org/10.1080/19336950.2018.1482183 · Published: May 22, 2018

Simple Explanation

Voltage-dependent calcium channels (CaV) activate over a wide range of membrane potentials, and the voltage-dependence of activation of specific channel isoforms is exquisitely tuned to their diverse functions in excitable cells. The study investigates how a specific molecular interaction, involving a negative countercharge (D4) in voltage-sensing domains (VSDs) of CaV1.2 and CaV1.3 channels, influences their gating properties. By neutralizing the charge of D4, researchers examined its role in voltage-sensing and channel gating, finding that it contributes to these processes in both CaV1.2 and CaV1.3, albeit to a lesser extent than in CaV1.1.

Study Duration

Not specified

Participants

Dysgenic myotubes expressing modified calcium channel constructs

Evidence Level

Not specified

Key Findings

1
In both CaV1.3 and CaV1.2 channels, a mutation neutralizing the D4 charge (D4N) in voltage-sensing domain IV (VSD IV) resulted in a right-shift of the voltage-dependence of activation by approximately 5 mV.
2
The D4N mutation also led to a reduction of current density to about half of that in control channels for both CaV1.3 and CaV1.2.
3
In CaV1.2, the effects of the D4N mutation were independent of alternative splicing, indicating that the two modulatory processes operate through distinct mechanisms.

Research Summary

This study investigates the role of a conserved negatively charged residue (D4) in the voltage-sensing domain IV (VSD IV) of CaV1.2 and CaV1.3 calcium channels, focusing on its impact on channel gating properties. The researchers found that neutralizing the charge of D4 in both CaV1.2 and CaV1.3 resulted in a right-shift of the voltage-dependence of activation and a reduction in current density, suggesting its involvement in voltage-sensing. The study concludes that while the D4-R1/R2 interaction in VSD IV contributes to voltage-sensing in all examined CaV1 channels, its role in regulating gating properties through alternative splicing is more prominent in the skeletal muscle CaV1.1 channel.

Practical Implications

Drug Targeting

Understanding the role of D4 in calcium channel gating may allow for more specific drug design targeting particular CaV subtypes.

Personalized Medicine

Given the impact of alternative splicing, personalized medicine approaches could benefit from understanding an individual's splice variants and their impact on channel function.

Channelopathies

The identification of D4 as a key residue in channel gating provides insights into the mechanisms underlying channelopathies related to CaV dysfunction.

Study Limitations

1
The study was conducted in dysgenic myotubes, which may not fully replicate the native environment of these channels.
2
The effects observed for CaV1.2 and CaV1.3 were smaller than those seen in CaV1.1, suggesting other factors may be at play.
3
The study focuses primarily on the D4 residue and its interaction with R1/R2, but other residues and interactions likely contribute to channel gating.

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