The family of nicotinic acetylcholine receptors supports chemical synaptic transmission throughout the nervous system, including efferent, or centrifugal regulation of the inner ear. While cholinergic innervation of the inner-ear has been studied in several animal models, our understanding of cholinergic transmission within the human inner ear is quite limited. We propose here to undertake molecular, electrophysiological and histological studies of a putative nicotinic receptor, alpha-9, in the human inner ear. This work will provide not only a molecular basis for the cholinergic modulation of human hair cells, but also will establish targets of novel therapies for diseases such as vertigo and tinnitus. Furthermore, mutations and disorders of nicotinic receptor function have been implicated in such diverse diseases as myasthenia gravis, nocturnal frontal lobe epilepsy and schizophrenia. Thus, the present work may also have wider implications for understanding otologic diseases without a known etiology, including autoimmune inner ear disorders or M ni re's syndrome. Recent work in our lab has led to the identification of the human ortholgue of alpha-9, included a complete elucidation of its cDNA and genomic sequence. The goal of the current research proposal is to fully characterize this newly identified receptor, which is a likely mediator of the efferent cholinergic response in the human inner-ear. Ongoing work during the initial characterization will include the search for splice variants within human tissue, as well as further genomic analysis of its regulatory elements. The second phase of the project will include the cellular localization of the alpha-9 gene product within surgically-derived hair populations and other tissue types. The third phase of the project will include functional expression of human alpha-9 to evaluate its physiologic response to acetylcholine and its antagonists. The final phase of the project will employ these same techniques in an effort to identify additional cholinergic receptor types that may be involved in efferent cholinergic transmission within the inner- ear.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Clinical Investigator Award (CIA) (K08)
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Communication Disorders Review Committee (CDRC)
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Sklare, Dan
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Johns Hopkins University
Schools of Medicine
United States
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Akil, Omar; Lustig, Lawrence R (2012) Severe vestibular dysfunction and altered vestibular innervation in mice lacking prosaposin. Neurosci Res 72:296-305
Akil, O; Weber, C M; Park, S N et al. (2008) Localization of synucleins in the mammalian cochlea. J Assoc Res Otolaryngol 9:452-63
Akil, Omar; Chang, Jolie; Hiel, Hakim et al. (2006) Progressive deafness and altered cochlear innervation in knock-out mice lacking prosaposin. J Neurosci 26:13076-88
Lustig, L R; Peng, H (2002) Chromosome location and characterization of the human nicotinic acetylcholine receptor subunit alpha (alpha) 9 (CHRNA9) gene. Cytogenet Genome Res 98:154-9