Tension Propagation Along Tip-Link Cadherins: Regulation and Implications for the Auditory System

Author

Daniel M. Firester

Date of Award

2021

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Hudspeth Laboratory

Abstract

Hair bundles detect sound by shearing in response to vibrations spanning orders of magnitude in intensity and frequency. Their responsiveness stems from mechanosensitive ion channels that sit atop the stereocilia and are gated by tension in tip links. Experimental evidence and theoretical arguments implicate a soft compliant element, with a stiffness of 1-4 mN/m, as necessary for mechanotransduction. Although the identity of this element remains an open question, direct measurements of a component of the tip link have highlighted entropic elasticity as one relevant characteristic. A tip link comprises a heterotetremer of protocadherin-15 and cadherin-23, arranged in a loose helical configuration and joined at their amino-terminals through a calcium ion dependent interaction. As for many other biopolymers, the tip link’s stiffness is several times greater than that of the empirically measured gating spring. To remain a viable candidate as a compliant element, entropic elasticity in the tip link must therefore be shown to support the full frequency and intensity range of auditory stimuli. In the present work, we model the tip link as a worm-like chain and evaluate its fast dynamic response using theoretical and numerical calculations. Our analysis uncovers frequencies at which the tip link exhibits viscoelastic behavior, and we evaluate how this behavior might alter auditory function. Critical to modulating the tip link’s frequency-dependent response is the resting tension, which controls both the frequency above which the tip link behaves viscoelastically and the tip-link’s local nonlinear stiffness. Under low resting tensions, we find that tension pools at the ends of the tip link and propagates poorly into the bulk of the chain. Upon application of high resting tensions, the frequency above which the tip link shows non-equilibrium behavior shifts beyond the range of human hearing.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Firester, Daniel M., "Tension Propagation Along Tip-Link Cadherins: Regulation and Implications for the Auditory System" (2021). Student Theses and Dissertations. 610.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/610