CA SENSING RECEPTOR · EXPLORING THE FUNCTION OF EXTERNAL CALCIUM DYNAMICS IN AUDITORY HAIR CELLS

Hair cells of the vertebrate cochlea have the remarkable property to transduce mechanical sound waves into electrical signals at the auditory nerve fibers. This sensory activity involves tightly regulated intracellular Ca2+ microdomains, both at the apical stereocilia level (Ca2+ influx through the mechano-sensitive channels) and the basolateral synaptic ribbon active zones (Ca2+ influx through L-type Ca2+ channels). Intense hair cell activity, that is spontaneous during development or evoked by sound stimulation in mature hair cells, should produce transient focal extracellular Ca2+changes ([Ca2+] ext) in the endolymph and synaptic clefts. The question of [Ca2+] ext signaling, while importantly addressed in central neurons, has never been investigated in auditory hair cells. Our preliminary results reveal for the first time a strong expression of the calcium sensing receptor (CaSR) in hair cells. CaSR is a G-protein-coupled membrane protein (GPCR) that detects small fluctuations in [Ca2+] ext. The goal of this application is to characterize the role of CaSR in mature and developing hair cell. We will develop a method for CaSR gene silencing using in-ovo electroporation in chick embryos. We will subsequently characterize any morphological and functional changes within the inner ear. Our proposed project could provide a novel view of Ca2+ homeostasis in the inner ear. This would increase our understanding of the function of Ca2+ signaling in the development of auditory system and maturation of hair cells. Interestingly, in humans, mutations in the gene coding for CaSR produce deafness. Thus, this study may also contribute to the treatment of hearing disorders whose pathology lies within the developing hair cells. This project and funding will serve as part of my training towards my goal of establishing my independent research in auditory physiology.