A Calmodulin C-Lobe Ca²⁺-Dependent Switch Governs Kv7 Channel Function.

Area of Science:

• Molecular and Cellular Biology
• Neuroscience
• Biophysics

Background:

• Kv7 (KCNQ) potassium channels are critical regulators of cellular excitability in the brain, heart, and ear.
• Calmodulin (CaM), a calcium sensor, is known to be essential for Kv7 channel function, but its precise regulatory mechanism remains elusive.

Purpose of the Study:

• To elucidate the structural and mechanistic basis of Calmodulin (CaM) regulation of Kv7.4 and Kv7.5 potassium channels.
• To establish a unified framework for understanding how CaM modulates different Kv7 channel isoforms.

Main Methods:

• X-ray crystallography was employed to determine the structures of CaM:Kv7.4 and CaM:Kv7.5 AB domain complexes.
• Small-angle X-ray scattering (SAXS), biochemical assays, and functional studies were integrated to characterize the CaM-Kv7 interaction.

Main Results:

• Structural analysis revealed a conserved Apo/CaM clamp conformation and specific calcium binding preferences for CaM with Kv7.4 and Kv7.5.
• A calcium-dependent switch in the CaM C-lobe was identified, which releases the clamp conformation.
• This switch inhibits Kv7.4 and Kv7.5 activation but facilitates Kv7.1 activation, demonstrating isoform-specific modulation via a shared mechanism.

Conclusions:

• A unified mechanism for CaM regulation of Kv7 channels is established, highlighting a conserved architecture with isoform-specific functional outcomes.
• The findings underscore the importance of membrane-proximal domains in controlling voltage-gated channel function and CaM modulation.
• This study provides critical insights into the role of CaM in regulating neuronal, cardiac, and auditory excitability via Kv7 channels.