Kv7-type Channel Currents in Spiral Ganglion Neurons

Abstract

Alterations in Kv7-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 Kv7.4 channels. Analyses of the cellular mechanisms of Kv7.4 mutations and progressive degeneration of SGNs have been hampered by the paucity of functional data on the role Kv7 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 Kv7-mediated currents.Wereport that differential contribution of Kv7 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 Ca2+ currents and a sustained rise in intracellular Ca2+. Using TUNEL assay, we demonstrate that a sustained increase in intracellular Ca2+ mediated by inhibition of Kv7 current results in significant SGN apoptotic death. Thus, this study provides evidence of the cellular etiology and mechanisms of SGN degeneration in DFNA2. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.