Tiplinks

Tiplinks are extracellular filaments in the sensory hair bundles of vertebrate inner-ear hair cells. They connect the tips of shorter stereocilia to the adjacent taller ones and form a crucial link in the mechanical to electrical transduction pathway that converts movement into neural signals.

The tip link is formed mainly by two cadherin-family proteins: protocadherin-15 (PCDH15) and cadherin-23 (CDH23). These proteins create a heterophilic connection, with PCDH15 at the lower tip of the shorter stereocilium and CDH23 at the upper end of the taller one. The bond is calcium-dependent and the tip link is coupled to the actin cytoskeleton through linker proteins and myosin motors, which helps regulate tension within the hair bundle.

Functionally, deflection of the hair bundle toward the tallest row tensions the tip link, opening nearby mechanotransduction (MET) channels and generating an inward current that depolarizes the hair cell. Deflection in the opposite direction relaxes the link and closes the channels, shaping the receptor potential in response to sound or head movement.

Tip links are sensitive to damage from loud noise and certain ototoxic agents, which can disrupt transduction and produce temporary or lasting hearing impairment. In mammals, tip links can regenerate over hours to days as CDH23 and PCDH15 are re-synthesized and re-established between stereocilia; the rate of recovery is influenced by species and conditions, with motor proteins and calcium-dependent adhesion contributing to tension regulation during repair.

Clinical significance includes mutations in CDH23 or PCDH15 causing hereditary deafness and Usher syndrome type 1. Experimental evidence includes disruption of MET currents by calcium chelators and localization studies supporting the proposed tip-link architecture.