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The Journal of Neuroscience, August 15, 2007, 27(33):8940-8951; doi:10.1523/JNEUROSCI.2085-07.2007

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Cellular/Molecular
Dominant-Negative Inhibition of M-Like Potassium Conductances in Hair Cells of the Mouse Inner Ear

Jeffrey R. Holt, Eric A. Stauffer, David Abraham, and Gwenaëlle S. G. Géléoc

Departments of Neuroscience and Otolaryngology, University of Virginia, Charlottesville, Virginia 22908

Correspondence should be addressed to Dr. Jeffrey R. Holt, Department of Neuroscience, University of Virginia, Medical Research Building 4, Room 5126, Box 801392, Charlottesville, VA 22908-1392. Email: jeffholt{at}virginia.edu

Sensory hair cells of the inner ear express multiple physiologically defined conductances, including mechanotransduction, Ca²⁺, Na⁺, and several distinct K⁺ conductances, all of which are critical for normal hearing and balance function. Yet, the molecular underpinnings and their specific contributions to sensory signaling in the inner ear remain obscure. We sought to identify hair-cell conductances mediated by KCNQ4, which, when mutated, causes the dominant progressive hearing loss DFNA2. We used the dominant-negative pore mutation G285S and packaged the coding sequence of KCNQ4 into adenoviral vectors. We transfected auditory and vestibular hair cells of organotypic cultures generated from the postnatal mouse inner ear. Cochlear outer hair cells and vestibular type I cells that expressed the transfection marker, green fluorescent protein, and the dominant-negative KCNQ4 construct lacked the M-like conductances that typify nontransfected control hair cells. As such, we conclude that the M-like conductances in mouse auditory and vestibular hair cells can include KCNQ4 subunits and may also include KCNQ4 coassembly partners. To examine the function of M-like conductances in hair cells, we recorded from cells transfected with mutant KCNQ4 and injected transduction current waveforms in current-clamp mode. Because the M-like conductances were active at rest, they contributed to the very low potassium-selective input resistance, which in turn hyperpolarized the resting potential and significantly attenuated the amplitude of the receptor potential. Modulation of M-like conductances may allow hair cells the ability to control the amplitude of their response to sensory stimuli.

Key words: potassium conductance; potassium channel; hair cell; utricle; saccule; semicircular canal; mechanotransduction; KCNQ

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Received April 6, 2007; revised June 28, 2007; accepted July 4, 2007.

Correspondence should be addressed to Dr. Jeffrey R. Holt, Department of Neuroscience, University of Virginia, Medical Research Building 4, Room 5126, Box 801392, Charlottesville, VA 22908-1392. Email: jeffholt{at}virginia.edu

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				A. D. Sousa, L. R. Andrade, F. T. Salles, A. M. Pillai, E. D. Buttermore, M. A. Bhat, and B. Kachar The Septate Junction Protein Caspr Is Required for Structural Support and Retention of KCNQ4 at Calyceal Synapses of Vestibular Hair Cells J. Neurosci., March 11, 2009; 29(10): 3103 - 3108. [Abstract] [Full Text] [PDF]

				D. A. Brown Kv7 (KCNQ) potassium channels that are mutated in human diseases J. Physiol., April 1, 2008; 586(7): 1781 - 1783. [Full Text] [PDF]

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