Auditory transduction depends critically on the Atp2b2 gene (encoding the PMCA2 protein). Our lab and others have identified several mutations in mouse and human genes (reviewed in Tempel and Shilling, 2007). We have developed an allelic series of deafwaddler mouse mutants with altered Atp2b2 that allow us to study the effects of stepwise reductions of functional PMCA2 in the cochlea. We have used this allelic series to show that heterozygous partial loss of function mutations are haplo-insufficient (McCullough and Tempel, 2004) and provide a model of age-related hearing loss (AHL) (McCullough and Tempel, 2005;Walker et al., 2008). In this proposal we will add to our knowledge of the role of PMCA2 in the cochlea by examining noise-induced hearing loss (NIHL) in alleles of deafwaddler. We will develop a new line of mice that over-express PMCA2 to see if these mice are resistant to AHL or NIHL. We will also study the role of PMCA2 in neurons of the auditory brainstem. We hypothesize that PMCA2 plays a critical role in regulating calcium (Ca2+) in these fast-firing neurons;a role previously unexplored because studies have focused on PMCA2 function in hair cells. Finally, we will develop a cellular expression system for studying PMCA2 function. We will use cysteine-scanning mutagenesis of PMCA2 to define sites where thiol reagents, when applied extracellularly can rapidly block Ca2+ pump activity. Besides providing insight into potential sites for drug targeting, this should provide a way to study the cellular role of PMCA2 in hair cell (HC) transduction and neuronal transmission. In an increasingly noisy and longer-lived society, knowledge of the genes contributing to age-related hearing loss and noise induced hearing loss is important. Our work on the plasma membrane calcium pump shows that it is localized to the stereocilia of the auditory hair cells and that when its function is reduced by mutations in mouse or human, they have significant hearing loss. We are studying how the calcium pump works, hoping to learn ways to make it protect hair cells from damage, thereby preventing hearing loss.
NARATIVE In an increasingly noisy and longer-lived society, knowledge of the genes contributing to age-related hearing loss and noise induced hearing loss is important. Our work on the plasma membrane calcium pump shows that it is localized to the stereocilia of the auditory hair cells and that when its function is reduced by mutations in mouse or human, they have significant hearing loss. We are studying how the calcium pump works, hoping to learn ways to make it protect hair cells from damage, thereby preventing hearing loss.
|Minich, Rebecca R; Li, Jin; Tempel, Bruce L (2017) Early growth response protein 1 regulates promoter activity of ?-plasma membrane calcium ATPase 2, a major calcium pump in the brain and auditory system. BMC Mol Biol 18:14|
|Peguero, Braulio; Tempel, Bruce L (2015) A Chromosome 17 Locus Engenders Frequency-Specific Non-Progressive Hearing Loss that Contributes to Age-Related Hearing Loss in Mice. J Assoc Res Otolaryngol 16:459-71|
|Kopp-Scheinpflug, Conny; Tempel, Bruce L (2015) Decreased temporal precision of neuronal signaling as a candidate mechanism of auditory processing disorder. Hear Res 330:213-20|
|Wang, Yuan; Sakano, Hitomi; Beebe, Karisa et al. (2014) Intense and specialized dendritic localization of the fragile X mental retardation protein in binaural brainstem neurons: a comparative study in the alligator, chicken, gerbil, and human. J Comp Neurol 522:2107-28|
|Watson, Claire J; Lies, Sarah M; Minich, Rebecca R et al. (2014) Changes in cochlear PMCA2 expression correlate with the maturation of auditory sensitivity. J Assoc Res Otolaryngol 15:543-54|
|Street, Valerie A; Kujawa, Sharon G; Manichaikul, Ani et al. (2014) Resistance to noise-induced hearing loss in 129S6 and MOLF mice: identification of independent, overlapping, and interacting chromosomal regions. J Assoc Res Otolaryngol 15:721-38|
|Watson, Claire J; Tempel, Bruce L (2013) A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers. Hear Res 304:41-8|
|Wang, Wenying; Kim, Hyo Jeong; Lv, Ping et al. (2013) Association of the Kv1 family of K+ channels and their functional blueprint in the properties of auditory neurons as revealed by genetic and functional analyses. J Neurophysiol 110:1751-64|
|McBride, Ethan G; Rubel, Edwin W; Wang, Yuan (2013) Afferent regulation of chicken auditory brainstem neurons: rapid changes in phosphorylation of elongation factor 2. J Comp Neurol 521:1165-83|
|Robbins, Carol A; Tempel, Bruce L (2012) Kv1.1 and Kv1.2: similar channels, different seizure models. Epilepsia 53 Suppl 1:134-41|
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