K Ramanathan

Johns Hopkins University, Baltimore, MD, United States

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Publications (3)41.6 Total impact

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    Krishnan Ramanathan, Paul A Fuchs
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    ABSTRACT: The receptor potential of sensory hair cells arises from the gating of mechanosensitive cation channels, but its amplitude and time course also depend on the number and kinetics of voltage-gated ion channels in each cell. Prominent among these are "BK" potassium channels encoded by the slo gene that support electrical tuning in some hair cells. Hair cells tuned to low frequencies have slowly gating BK channels, whereas those of higher-frequency hair cells gate more rapidly. Alternative splicing of the slo gene mRNA that encodes the pore-forming alpha subunit can alter BK channel kinetics, and gating is dramatically slowed by coexpression with modulatory beta subunits. The effect of the beta subunit is consistent with low-frequency tuning, and beta mRNA is expressed at highest levels in the low frequency apex of the bird's auditory epithelium. How might an expression gradient of beta subunits contribute to hair cell tuning? The present work uses a computational model of hair cell-tuning based on the functional properties of BK channels expressed from hair cell alpha and beta slo cDNA. The model reveals that a limited tonotopic gradient could be achieved simply by altering the fraction of BK channels in each hair cell that are combined with beta subunits. However, complete coverage of the tuning spectrum requires kinetic variants in addition to those modeled here.
    Biophysical Journal 02/2002; 82(1 Pt 1):64-75. · 3.67 Impact Factor
  • Source
    K Ramanathan, T H Michael, P A Fuchs
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    ABSTRACT: Electrical tuning confers frequency selectivity onto sensory hair cells in the auditory periphery of frogs, turtles, and chicks. The resonant frequency is determined in large part by the number and kinetics of large conductance, calcium-activated potassium (BK) channels. BK channels in hair cells are encoded by the alternatively spliced slo gene and may include an accessory beta subunit. Here we examine the origins of kinetic variability among BK channels by heterologous expression of avian cochlear slo cDNAs. Four alternatively spliced forms of the slo-alpha gene from chick hair cells were co-expressed with accessory beta subunits (from quail cochlea) by transient transfection of human embryonic kidney 293 cells. Addition of the beta subunit increased steady-state calcium affinity, raised the Hill coefficient for calcium binding, and slowed channel deactivation rates, resulting in eight functionally distinct channels. For example, a naturally occurring splice variant containing three additional exons deactivated 20-fold more slowly when combined with beta. Deactivation kinetics were used to predict tuning frequencies and thus tonotopic location if hair cells were endowed with each of the expressed channels. All beta-containing channels were predicted to lie within the apical (low-frequency) 30% of the epithelium, consistent with previous in situ hybridization studies. Individual slo-alpha exons would be found anywhere within the apical 70%, depending on the presence of beta, and other alternative exons. Alternative splicing of the slo-alpha channel message provides intrinsic variability in gating kinetics that is expanded to a wider range of tuning by modulation with beta subunits.
    Journal of Neuroscience 04/2000; 20(5):1675-84. · 6.91 Impact Factor
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    ABSTRACT: Cochlear frequency selectivity in lower vertebrates arises in part from electrical tuning intrinsic to the sensory hair cells. The resonant frequency is determined largely by the gating kinetics of calcium-activated potassium (BK) channels encoded by the slo gene. Alternative splicing of slo from chick cochlea generated kinetically distinct BK channels. Combination with accessory beta subunits slowed the gating kinetics of alpha splice variants but preserved relative differences between them. In situ hybridization showed that the beta subunit is preferentially expressed by low-frequency (apical) hair cells in the avian cochlea. Interaction of beta with alpha splice variants could provide the kinetic range needed for electrical tuning of cochlear hair cells.
    Science 02/1999; 283(5399):215-7. · 31.03 Impact Factor

Publication Stats

173 Citations
41.60 Total Impact Points

Institutions

  • 1999–2002
    • Johns Hopkins University
      • Department of Biomedical Engineering
      Baltimore, MD, United States