Endocochlear potential (EP) (> 80 mV) is a requisite for normal sound transduction. The significance of EP to normal hearing is underpinned by the evidence that in most animal models of age-related hearing loss the hearing threshold/sensitivity is directly related to EP at ~1 dB/mV. Recent reports have identified a novel K+ channel, (TWIK-1 or KCNK1), with unknown functions in the inner ear that are expressed at high densities at the apical membrane of marginal cells (MCs). Because the TWIK-1 is non-voltage-gated, it should serve as a background current to promote high K+ throughput. We have also identified and cloned an inner ear lateral wall-specific K+ channel, MERG1a, which is poised in the strial vascularis (StV) to contribute towards K+ flux. Last, it is thought that a major channel involved in the high throughput of outward K+ movement across the intermediate cells (ICs) to generate EP is the Kir4.1 channel. Paradoxically, Kir4.1 is an inward rectifying K+ channels (Kir). Moreover, we have also identified other inward rectifier channel subtypes, Kir4.2 and Kir5.1 that may form functional heteromultimers with Kir4.1 in the StV. We hypothesize that EP is produced and maintained by a cadre of K+ channels in the apical membrane of ICs and MCs as well as basolateral Cl- channels in conjunction with NKCC1 and Na+/K+ ATPase. We will determine the properties of K+ and Cl- conductances in their native settings in cells of the StV. In addition, we will clone and examine cochlear lateral wall (LW)-specific K+ and Cl- channels using a variety of molecular biological, biochemical and functional techniques. The channel properties will be studied in detail in vitro. Last, we will identify the functional role of the channels, in vivo, by crippling the functions of the channels using cell-specific dominant-negative (DN) strategies in the StV in mice. Collectively, these studies will substantially expand our understanding of the specific functions of individual K+ and Cl- channels, as well as the different cell types in the StV, and how they work together to mediate EP and transepithelial ion transport processes in vivo.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (91))
Program Officer
Donahue, Amy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Medicine
United States
Zip Code
Sirish, Padmini; Ledford, Hannah A; Timofeyev, Valeriy et al. (2017) Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6. Circ Arrhythm Electrophysiol 10:
Sirish, Padmini; Li, Ning; Timofeyev, Valeriy et al. (2016) Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. Circ Arrhythm Electrophysiol 9:
Levic, Snezana; Yamoah, Ebenezer N (2016) Method for Dissecting the Auditory Epithelium (Basilar Papilla) in Developing Chick Embryos. Methods Mol Biol 1427:463-70
Sihn, Choong-Ryoul; Kim, Hyo Jeong; Woltz, Ryan L et al. (2016) Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels. J Biol Chem 291:2499-509
Wang, Wenying; Flores, Maria Cristina Perez; Sihn, Choong-Ryoul et al. (2015) Identification of a key residue in Kv7.1 potassium channel essential for sensing external potassium ions. J Gen Physiol 145:201-12
Lu, Ling; Sirish, Padmini; Zhang, Zheng et al. (2015) Regulation of gene transcription by voltage-gated L-type calcium channel, Cav1.3. J Biol Chem 290:4663-76
Rafizadeh, Sassan; Zhang, Zheng; Woltz, Ryan L et al. (2014) Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca2+-activated K+ (SK2) channel. Proc Natl Acad Sci U S A 111:9989-94
Kim, Hyo Jeong; Gratton, Michael Anne; Lee, Jeong-Han et al. (2013) Precise toxigenic ablation of intermediate cells abolishes the ""battery"" of the cochlear duct. J Neurosci 33:14601-6
Cao, Lin; Wei, Dongguang; Reid, Brian et al. (2013) Endogenous electric currents might guide rostral migration of neuroblasts. EMBO Rep 14:184-90
Kim, Hyo Jeong; Lv, Ping; Sihn, Choong-Ryoul et al. (2011) Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2. J Biol Chem 286:1517-27

Showing the most recent 10 out of 26 publications