MDFIC2 is a sensory neuron-specific PIEZO channel auxiliary subunit

Area of Science:

• Cellular mechanobiology
• Ion channel regulation
• Sensory neuroscience

Background:

• PIEZO channels are essential for converting mechanical stimuli into cellular signals.
• MyoD-family inhibitor proteins (MDFIC, MDFI) were known to regulate PIEZO1, but their role in sensory cells was unknown.

Purpose of the Study:

• To investigate the role of MyoD-family inhibitor proteins in PIEZO channel regulation, particularly in sensory neurons.
• To identify novel regulators of PIEZO channels in sensory cells.

Main Methods:

• Electrophysiology to measure PIEZO channel currents.
• Co-immunoprecipitation to assess protein binding.
• Cryo-electron microscopy (cryo-EM) for structural analysis.
• Analysis of gene expression in sensory neurons.

Main Results:

• MDFIC and MDFI regulate PIEZO channels in non-sensory cells.
• A novel protein, MDFIC2, is expressed in sensory neurons and binds PIEZO1 and PIEZO2.
• MDFIC2 modifies PIEZO channel gating kinetics, creating high-threshold mechanoreceptors.
• Cryo-EM revealed a conserved binding site for these proteins on PIEZO channels.

Conclusions:

• MyoD-family inhibitor proteins, including the novel MDFIC2, act as crucial auxiliary subunits for PIEZO1 and PIEZO2 channels.
• These interactions are vital for tuning mechanosensitivity in both non-sensory and sensory cells.
• Structural insights into the PIEZO-MDFIC interaction provide a foundation for understanding mechanobiology.