Kv7-type channel currents in spiral ganglion neurons: involvement in sensorineural hearing loss.

Alterations in K(v)7-mediated currents in excitable cells result in several diseased conditions. A case in DFNA2, an autosomal dominant version of progressive hearing loss, involves degeneration of hair cells and spiral ganglion neurons (SGNs) from basal to apical cochlea, manifesting as high-to-low frequency hearing loss, and has been ascribed to mutations in K(v)7.4 channels. Analyses of the cellular mechanisms of K(v)7.4 mutations and progressive degeneration of SGNs have been hampered by the paucity of functional data on the role K(v)7 channels play in young and adult neurons. To understand the cellular mechanisms of the disease in SGNs, we examined temporal (young, 0.5 months old, and senescent, 17 months old) and spatial (apical and basal) roles of K(v)7-mediated currents. We report that differential contribution of K(v)7 currents in mice SGNs results in distinct and profound variations of the membrane properties of basal versus apical neurons. The current produces a major impact on the resting membrane potential of basal neurons. Inhibition of the current promotes membrane depolarization, resulting in activation of Ca(2+) currents and a sustained rise in intracellular Ca(2+). Using TUNEL assay, we demonstrate that a sustained increase in intracellular Ca(2+) mediated by inhibition of K(v)7 current results in significant SGN apoptotic death. Thus, this study provides evidence of the cellular etiology and mechanisms of SGN degeneration in DFNA2.