Clues to the mystery of hearing’s molecular mechanisms

About the School of Medicine Paper of the Month

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Senior Associate Dean for Research Mary Stenzel-Poore, Ph.D., Associate Dean for Clinical Science Eric Orwoll, M.D., and Assistant Dean for Basic Research Mary Heinricher, Ph.D.

September 29, 2014

September's featured paper is called “Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2,” published in the journal The Proceedings of the National Academy of Sciences by the Barr-Gillespie and Nicolson laboratories.

Your ears are amazing organs that transform sound waves into neurological signals. Sound waves travel in the ear canal until they reach the eardrum, which passes vibrations through the middle ear bones to the inner ear. Inside the inner ear, thousands of tiny hair cells detect vibrations and ultimately turn a mechanical signal (air vibrations) into a neurological signal. 

“We have come far in understanding how the external world gets transduced into neural activity that forms a picture of the outside world,” said Mary Heinricher, Ph.D., assistant dean for basic research.  “Even just 10 years ago, we could identify the sensory cells that converted light or sound waves or touch into neuronal signals (mechanotransduction), but the molecular mechanisms that gave the different sensory systems their selectivity and sensitivity were a mystery.”

This month’s featured paper, produced by the Barr-Gillespie and Nicolson laboratories, takes tremendous strides towards better understanding the molecular mechanisms that drive vestibular and auditory perception.

nicolson web

An important role

Previous studies had shown that protocadherin 15 (PCDH15) plays an important role in the detection of sound and head movements.

“Protocadherins are widespread in the nervous system and normally participate in cell adhesion,” said Teresa Nicolson, Ph.D., adjunct associate professor of otolaryngology and head and neck surgery,  member of the Oregon Hearing Research Institute and scientist at the Vollum Institute. “In hair cells, PCDH15 is part of the tip link structure that mediates mechanotransduction. How PCDH15 is coupled to the mechanosensory machinery is not clear, and the identity of the mechanotransduction channels are still up in the air.”

Peter Barr-Gillespie, Ph.D., professor of otolaryngology and head and neck surgery and senior scientist at the Vollum Institute, added, “We know that PCDH15 can interact with cytosolic proteins involved with Usher syndrome type I, which causes profound deafness and progressive vision loss.  Another interacting protein is called Transmembrane hair cell stereocilia protein (TMHS).  Although TMHS spans the membrane several times, is not thought to be a transduction channel.”

First evidence

In order to identify key components of the transduction complex in hair cells, the Nicolson lab performed an unbiased membrane-based screen with zebrafish Pcdh15a. 

“We detected an interaction with transmembrane channel like 2a (Tmc2a), an orthologue of mammalian TMC2”, said Dr. Nicolson. “In collaboration with Peter’s laboratory, we found that the PCDH15-TMC interactions were conserved among the mammalian orthologues. We also demonstrated the in vivo relevance of the interaction in zebrafish hair cells.”

“Mutations in the genes for TMC1 and TMC2 cause hearing loss, and several laboratories have argued that the TMCs make up the transduction channel,” said Dr. Barr-Gillespie. “Close study of TMC mutants showed that regardless of whether the TMCs are the transduction channel, they are intimately related with the channel and so they’re another key component of the transduction machinery.”

“Our work provides the first evidence of a biochemical interaction between a tip link protein (PCDH15) and a TMC family member,” said Dr. Nicolson.  “It is compelling evidence in support of the hypothesis that TMC1 and TMC2 are critical components of the mechanotransduction complex in hair cells.” 

Dr. Heinricher added, “I selected this paper not only because it provides the first evidence linking interactions between TCMs and PCDH15, but also because it is an example of the incredibly sophisticated methods that we can now bring to address these questions.” 

Dr. Nicolson plans to continue this research, moving on to characterize zebrafish tmc mutants, and study structure/function relationships. 

“Not much is known about the various motifs or domains within the TMC proteins,” said Dr. Nicolson. “We will also further characterize proteins that interact with TMC1 and TMC2 in collaboration with Peter’s laboratory because co-expression of these proteins may be key to reconstituting the mechanotransduction complex.” 

Drs. Nicolson and Barr-Gillespie will continue to be leaders in hearing research, and their work will continue to expand our understanding of the molecular mechanisms of hearing.

•    Read the paper
•    Read about the Nicolson Lab


Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2.Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12907-12
Reo Maeda, Katie S. Kindt, Weike Mo, Clive P. Morgan, Timothy Erickson, Hongyu Zhao, Rachel Clemens-Grisham, Peter G. Barr-Gillespie, and Teresa Nicolson

More published papers

•    Previous School of Medicine Papers of the Month
•    Recent OHSU published papers

Pictured above from left to right: Peter Barr-Gillespie, Reo Maeda, Timothy Erickson, Teresa Nicolson, Clive Morgan