Mutations in PMCA2 and hereditary deafness: A molecular analysis of the pump defect

The inner ear converts sound waves into hearing signals through the mechanoelectrical transduction (MET) process. Deflection of the stereocilia bundle of hair cells causes the opening of channels that allow the entry of endolymph K+ and Ca2+. Ca2+ that enters is crucial to the hearing process and is exported to the endolymph by the plasma membrane Ca2+ pump (isoform PMCA2w/a): disturbances of the balance between Ca2+ penetration and ejection, e.g. by pump mutations, generate deafness. Hearing loss caused by PMCA defects is frequently exacerbated by mutations in cadherin 23, a single pass stereociliar Ca2+ binding protein that forms the tip links which permit the deflection of the stereocilia bundle and thus the opening of the MET channels. The PMCA2w/a pump ejects Ca2+ to the endolymph even in the absence of the natural activator calmodulin. This satisfies the special Ca2+ homeostasis requirements of the stereocilia/endolymph system. Here we have analyzed a mice and a human previously described pump mutant. The human mutant only exacerbated the deafness produced by a cadherin 23 mutation. The murine mutant overexpressed in model cells displayed an evident defect both in the basal activity of the pump and in the long range ejection of Ca2+, the human mutant instead failed to impair the Ca2+ ejection by the pump.