HAIR CELL POTASIUM CHANNELS-- MARKERS OF DIFFERENTIATION

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION: (Adapted from the applicant's abstract) Hair cells show a remarkable variability in their membrane conductances along the tonotopic axis of a hearing organ. The long-term objectives are to determine the molecular basis for this heterogeneity and to ascertain the mechanisms responsible for its generation and maintenance. Using the chick basilar papilla as a model system, Dr. Oberholtzer has cloned four potassium channel genes, three of which (cSlo, cIRK1, and cKv3.1) encode channels previously shown to be differentially distributed. cSlo is extensively alternatively spliced, providing one mechanism for the functional heterogeneity of BK potassium currents carried by the channel gene's gene product. To determine how cSlo heterogeneity supports frequency cloning, the investigators will determine the native cSlo transcript isoforms that are expressed in the basilar papilla. Because the functional properties of cSlo may be modified by cSlack, they will determine the functional properties of cSlack alone and in combination with cSlo. Heterogeneity in expression of cIRK1 and cKv3.1 in the basilar papilla does not arise from alternative splicing, but rather by selective expression only in the apical half of the papilla. To dissect the mechanism involved in tonotopic expression restriction, the investigators will characterize in vitro the promoter and upstream sequences of cIRK1 that may play a role in expression restriction. To extend these studies into the context of native hair-cell chromatin, the investigators will determine in vivo the relevance of candidate cIRK1 5'-flanking control regions by analyzing the endogenous locus. The results obtained should provide insight to those interested in peripheral auditory system function, as well as to those interested in understanding mechanisms of gene regulation.