Roles of Volume-Regulated Anion Channels (VRACs) in Drug-Induced Ototoxicity and the Hair-Cell Damage Repair Response

The anti-cancer reagent cisplatin and the aminoglycoside antibiotics are ototoxins that lead to the irreversible loss of sensory hair cells from the cochlea.

Whilst well established that the mechano-electrical transducer (MET) channels are the principal route whereby the aminoglycosides selectively enter into and accumulate in hair cells, it is far less certain that cisplatin follows the same pathway.

Alternative ports of entry include the organic cation transporter OCT2, the copper transporter CTR1, and the volume-regulated anion channels (VRACs).

For the latter it is known that cancer cells lacking the leucine rich repeat containing subunit LRRC8D of the VRAC are resistant to cisplatin treatment.

Published and preliminary data indicate that (i) Lrrc8D and the protein it encodes are expressed in hair cells, (ii) VRAC currents in hair cells are blocked by neomycin, and (iii) VRAC inhibitors prevent a previously described damage-repair process that is initiated in hair cells following their transient exposure to high levels of neomycin.

Transient neomycin exposure also enhances the subsequent loading of hair cells with gentamicin conjugated to Texas Red (GTTR).

The principal aims of the project are (1) to characterize the electrophysiological properties of VRACs in hair cells, (2) to establish whether hair cells lacking LRRC8D are resistant to cisplatin toxicity, (3) to determine if re-activation of VRACs following transient neomycin exposure drives a previously described plasma membrane recovery process known as massive endocytosis (MEND), and (4) to ascertain if transient exposure to neomycin or cisplatin enhances subsequent drug loading by increasing VRAC currents.