The primary sensory cell of the inner ear (the hair cell) releases a neurotransmitter to excite auditory nerve fibers. The identification of this transmitter, which may not be one of the known neurotransmitters, is the goal of this project. We have purified, from hair cell tissue and from retina, a substance that can excite afferent nerve fibers innervating hair cells. This substance appears to be a potent, unstable, unknown excitatory amino acid with pharmacological activity similar to glutamate; however, it is clearly not glutamate or any other commonly studied substance. Application of gas chromatography/mass spectroscopy to the purified excitatory substance has revealed a candidate compound that may be directly related to this unknown excitatory substance. This compound copurifies with the major excitatory substance through three very different chromatographic purification steps (gel-permeation chromatography, anion-exchange HPLC, and cation-exchange HPLC). The goals during this project period are to identify the chemical structure of the excitatory substance, to analyze its distribution in hair cell organs and in the nervous system, and to determine its role in hair cell organ function. In addition to the intrinsic intellectual importance of identifying the neurotransmitter released by hair cells, this work may have significant practical implications for otolaryngology and should have widespread importance for areas of neurobiology beyond the auditory system. Once the biochemical and physiological systems necessary for making and releasing such a substance are understood, a number of research tools, including molecular biological approaches, can be brought to bear on understanding whether defects in the processes are involved in pathological processes in auditory function. Drugs differing slightly in structure can be devised which might selectively block transmission at this synapse. If it is possible to develop drugs with some specificity for vestibular fibers, a treatment for motion sickness and intractable vertigo would likely result. Judicious use of a drug with specificity for the auditory system might alleviate some forms of peripheral tinnitus. The excitatory amino acid we have isolated from hair cell tissue and from retina is a good candidate to be a neurotransmitter in other pans of the nervous system; we already know it is concentrated in inner ear and in retina. If it is localized discretely within the nervous system, it will almost assuredly provide a means of selectively studying transmission and function of other regions of the nervous system.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
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Special Emphasis Panel (ZRG1-CMS (01))
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Massachusetts Eye and Ear Infirmary
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Kantardzhieva, Albena; Liberman, M Charles; Sewell, William F (2013) Quantitative analysis of ribbons, vesicles, and cisterns at the cat inner hair cell synapse: correlations with spontaneous rate. J Comp Neurol 521:3260-71
Peppi, Marcello; Landa, Melissa; Sewell, William F (2012) Cochlear kainate receptors. J Assoc Res Otolaryngol 13:199-208
Kantardzhieva, A; Peppi, M; Lane, W S et al. (2012) Protein composition of immunoprecipitated synaptic ribbons. J Proteome Res 11:1163-74
Peppi, Marcello; Kujawa, Sharon G; Sewell, William F (2011) A corticosteroid-responsive transcription factor, promyelocytic leukemia zinc finger protein, mediates protection of the cochlea from acoustic trauma. J Neurosci 31:735-41
Chen, Zhiqiang; Peppi, Marcello; Kujawa, Sharon G et al. (2009) Regulated expression of surface AMPA receptors reduces excitotoxicity in auditory neurons. J Neurophysiol 102:1152-9
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Sewell, W F; Mroz, E A; Evans, J E (2005) Extracts of retina and brain that excite afferent fibers innervating hair cells contain a compound related to hydroxyphenylglycine-N-carbamoyl. Synapse 58:129-40
Dawkins, Rosie; Keller, Sarah L; Sewell, William F (2005) Pharmacology of acetylcholine-mediated cell signaling in the lateral line organ following efferent stimulation. J Neurophysiol 93:2541-51
Chen, Zhiqiang; Kujawa, Sharon G; McKenna, Michael J et al. (2005) Inner ear drug delivery via a reciprocating perfusion system in the guinea pig. J Control Release 110:1-19
Dawkins, Rosie; Sewell, William F (2004) Afferent synaptic transmission in a hair cell organ: pharmacological and physiological analysis of the role of the extended refractory period. J Neurophysiol 92:1105-15

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