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Functional Significance of K+ Channel β-Subunit KCNE3 in Auditory Neurons.
Wenying Wang, Hyo Jeong Kim, Jeong-Han Lee, Victor Wong, Choong-Ryoul Sihn, Ping Lv, Cristina Maria Perez Flores, Atefeh Mousavi-Nik, Karen Jo Doyle, Yanfang Xu, Ebenezer N Yamoah
J. Biol. Chem.,
The KCNE3 β-subunit interacts with and regulates the voltage-dependent gating, kinetics and pharmacology of a variety of Kv channels in neurons. Because a single neuron may express multiple KCNE3 partners, it is impossible to predict the overall functional relevance of the single transmembrane-domain peptide on the pore-forming K+ channel subunits that it associates with. In the inner ear, the role of KCNE3 is undefined, despite its association with Meniere's disease and tinnitus. To gain insights on the functional significance of KCNE3 in auditory neurons, we examined the properties of spiral ganglion neurons (SGNs) in Kcne3 null mutant neurons relative to their age-matched controls. We demonstrate that null deletion of Kcne3 abolishes characteristic wide-variations in the resting membrane potentials (RMPs) of SGNs, and yields age-dependent alterations in action potential (AP) and firing properties of neurons along the contour of the cochlear axis, in comparison with age-matched wild-type neurons. The properties of basal SGNs were markedly altered in Kcne3-/- mice compared with the wild-type controls; these include reduced AP latency, amplitude and increased firing frequency. Analyses of the underlying conductance demonstrate that null mutation of Kcne3 results in enhanced outward K+ currents, which is sufficient to explain the ensuing membrane potential changes. Additionally, we have demonstrated the KCNE3 may regulate the activity of Kv4.2 channels in SGNs. Finally, there were developmentally-mediated compensatory changes that occurred such that by 8 weeks after birth, the electrical properties of the null mutant neurons were virtually indistinguishable from the wild-type neurons, suggesting that ion channel remodeling in auditory neurons progresses beyond hearing onset.