Missing link in puzzle of how hearing work found by MRC Laboratory of Molecular Biology

Missing pieces to the puzzle of how hearing works at the basic molecular level have been identified by scientists at the MRC Laboratory of Molecular Biology.

It is hoped that studying how these key proteins work together to detect sound vibrations and exploring why they might stop working in disease could lead to better understanding of hearing loss - and ultimately lead to treatment.

Hearing and touch rely on the ability of sensory neurons to be activated by a force, such as pressure or vibration from sound.

The process is known as mechanotransduction and involves the sensory neuron responding to this mechanical force by opening specialised ion channels, prompting the neuron to fire an electrical signal.

Scientists have been aware of many of these mechanotransduction ion channels, but have not properly understood how they are controlled by force.

Now the group of newly-elected Royal Society fellow William Schafer, in the LMB’s Neurobiology Division, has identified some the elusive proteins that act as a molecular connection between this mechanical stimulus - sound or touch - and a nerve firing.

One model suggests an elastic filament, known as a gating spring, tethers the ion channel to the cell’s internal cytoskeleton. This allows external forces to be connected through to the channel via movement of the cytoskeleton.

But the identity of the gating spring was not known.

Now postdoctoral researcher Yiquan Tang has identified two proteins necessary for the function of mechanotransduction channels in C. elegans worms - CALM-1 and UNC-44.

Through collaboration with Hang Lu’s group at Georgia Tech and Siva Vanapalli’s group at Texas Tech University, the roles of these proteins in mechanosensation was uncovered.

The researchers measured responses to applied mechanical forces and forces generated by the muscles of mutant and normal worms.

UNC-44 is the worm version of a protein family called ankyrins, which are elastic filamentous proteins that interact with the cytoskeleton and so could fulfil the role of a gating spring.

Yiquan found UNC-44 interacts with CALM-1 and CALM-1 binds to mechanotransduction channels.

This suggests CALM-1 acts as an adaptor to link the gating spring ankyrin to the channel, completing the chain link from cytoskeleton to ion channel.

The same complex is used to detect force in muscle cells - demonstrating that the same molecular machines can be used in seemingly unrelated biological processes.

CALM-1 is the worm version of the human CIB2 protein, and mutations in this have been associated with deafness, suggesting this complex might be conserved and ankyrin might act as the gating spring to allow hearing and touch sensation in humans.

The work was funded by UKRI MRC, the Wellcome Trust, NIH, NASA, and the Cancer Prevention and Research Institute of Texas.

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