Hearing loss affects tens of millions of Americans. For many of these individuals, the deficit arises from damage to hair cells. Hair cells are the sensory cells of the inner car; they are essential for our appreciation of sound and our sense of balance. Voltage-gated calcium (Ca) channels (VGCC) play several important roles in hair-cell functions. In fact, hearing and balance disorders, e.g. Meniere's disease, may result from VGCC dysfunction. Ca influx through the VGCC represents the principal source of Ca in hair cells. Previous studies have suggested that hair cells express only L-type Ca channels and concluded that this Ca channel subtype controls neurotransmitter release and activation of potassium (K) channels, which mediate electrical tuning in lower vertebrates. However, the properties of these channels, which render the diverse roles of Ca are unknown. Contrary to previous investigations that suggested a single Ca channel subtype, we have recently obtained physiological data which suggest that hair cells may express more than one type of Ca channel. We hypothesize that hair cells may express two classes of Ca channels (L- and non-L-type channels) to produce multiple Ca-dependent processes. Whereas the L-type Ca channels may mediate the activation of K channels, the L-type channels may trigger neurotransmitter release. Alternatively, the L-type channel may mediate evoked neurotransmitter release while the non L-type channel may trigger tonic neurotransmitter release. However, we predict that there will be functional overlap of the two Ca channel subtypes because of similar voltage-dependent properties and co-localization of the two channels. We further hypothesize that Ca channel clusters may consist of more than one channel subtype. Finally, we hypothesize that membrane cytoskeleton (e.g. actin) may be involved in Ca channel clustering. We will test these hypotheses, using hair cells from the bullfrog saccule and chicken basilar papilla. These studies will provide invaluable information on the properties of Ca channels that confer hair cell functions. Through these studies, rational design of Ca channel subtype-specific drugs may be realized as our understanding of the gating, permeation and pharmacology of Ca channels becomes more defined.
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