KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway.

Mutations in the potassium channel gene KCNQ4 underlie DFNA2, an autosomal dominant form of progressive hearing loss in humans. In the mouse cochlea, the transcript has been found exclusively in the outer hair cells. By using specific antibodies, we now show that KCNQ4 is situated at the basal membrane of these sensory cells. In the vestibular organs, KCNQ4 is restricted to the type I hair cells and the afferent calyx-like nerve endings ensheathing these sensory cells. Several lines of evidence suggest that KCNQ4 underlies the I(K,n) and g(K,L) currents that have been described in the outer and type I hair cells, respectively, and that are already open at resting potentials. KCNQ4 is also expressed in neurons of many, but not all, nuclei of the central auditory pathway, and is absent from most other brain regions. It is present, e.g., in the cochlear nuclei, the nuclei of the lateral lemniscus, and the inferior colliculus. This is the first ion channel shown to be specifically expressed in a sensory pathway. Moreover, the expression pattern of KCNQ4 in the mouse auditory system raises the possibility of a central component in the DFNA2 hearing loss.

[1]  Laurence O Trussell,et al.  Cellular mechanisms for preservation of timing in central auditory pathways , 1997, Current Opinion in Neurobiology.

[2]  J F Ashmore,et al.  Ionic currents of outer hair cells isolated from the guinea‐pig cochlea. , 1992, The Journal of physiology.

[3]  G Van Camp,et al.  Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. , 1999, Human molecular genetics.

[4]  R. Eatock,et al.  A delayed rectifier conductance in type I hair cells of the mouse utricle. , 1996, Journal of neurophysiology.

[5]  C. Petit Genes responsible for human hereditary deafness: symphony of a thousand , 1996, Nature Genetics.

[6]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[7]  N. Mizuno,et al.  Single neurons in the spinal trigeminal and dorsal column nuclei project to both the cochlear nucleus and the inferior colliculus by way of axon collaterals: a fluorescent retrograde double-labeling study in the rat , 1997, Neuroscience Research.

[8]  O. Ottersen,et al.  Organization of AMPA Receptor Subunits at a Glutamate Synapse: A Quantitative Immunogold Analysis of Hair Cell Synapses in the Rat Organ of Corti , 1996, The Journal of Neuroscience.

[9]  Renato Nobili,et al.  How well do we understand the cochlea? , 1998, Trends in Neurosciences.

[10]  R. Petralia,et al.  Endbulb Synapses in the Anteroventral Cochlear Nucleus Express a Specific Subset of AMPA-Type Glutamate Receptor Subunits , 1998, The Journal of Neuroscience.

[11]  F Mammano,et al.  Differential expression of outer hair cell potassium currents in the isolated cochlea of the guinea‐pig. , 1996, The Journal of physiology.

[12]  K. Steel,et al.  Genes involved in deafness. , 1999, Current opinion in genetics & development.

[13]  J. Goldberg,et al.  A regional ultrastructural analysis of the cellular and synaptic architecture in the chinchilla cristae ampullares , 1997, The Journal of comparative neurology.

[14]  A. Hudspeth,et al.  Mechanical amplification of stimuli by hair cells , 1997, Current Opinion in Neurobiology.

[15]  J. Ostwald,et al.  Afferent and efferent connections of the ventrolateral tegmental area in the rat , 1997, Anatomy and Embryology.

[16]  S. Komune,et al.  Ionic properties of I K,n in outer hair cells of guinea pig cochlea , 1994, Brain Research.

[17]  Thomas Friedrich,et al.  KCNQ4, a Novel Potassium Channel Expressed in Sensory Outer Hair Cells, Is Mutated in Dominant Deafness , 1999, Cell.

[18]  P. Dallos,et al.  Effect of absence of cochlear outer hair cells on behavioural auditory threshold , 1975, Nature.

[19]  S. Berkovic,et al.  A potassium channel mutation in neonatal human epilepsy. , 1998, Science.

[20]  E Friauf,et al.  Giant neurons in the rat reticular formation: a sensorimotor interface in the elementary acoustic startle circuit? , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  D. Fekete Development of the vertebrate ear: insights from knockouts and mutants , 1999, Trends in Neurosciences.

[22]  Immunocytochemical localization of intermediate filaments in the guinea pig vestibular periphery with special reference to their alteration after ototoxic drug administration. , 1993, Acta oto-laryngologica. Supplementum.

[23]  J. Goldberg Theoretical analysis of intercellular communication between the vestibular type I hair cell and its calyx ending. , 1996, Journal of neurophysiology.

[24]  C. Petit,et al.  The fundamental and medical impacts of recent progress in research on hereditary hearing loss. , 1998, Human molecular genetics.

[25]  L. Kaczmarek,et al.  Contribution of the Kv3.1 potassium channel to high‐frequency firing in mouse auditory neurones , 1998, The Journal of physiology.

[26]  L. Trussell,et al.  Synaptic mechanisms for coding timing in auditory neurons. , 1999, Annual review of physiology.

[27]  B S Brown,et al.  KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. , 1998, Science.

[28]  W. M. Roberts,et al.  Electrical Properties of Frog Saccular Hair Cells: Distortion by Enzymatic Dissociation , 1998, The Journal of Neuroscience.

[29]  H. Herbert,et al.  Distribution and origin of noradrenergic and serotonergic fibers in the cochlear nucleus and inferior colliculus of the rat , 1991, Brain Research.

[30]  C. Cremers,et al.  Nonsyndromic Autosomal Dominant Progressive Sensorineural Hearing Loss: Audiologic Analysis of a Pedigree Linked to DFNA2 , 1998, The Laryngoscope.

[31]  C. Kubisch,et al.  Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy , 1998, Nature.

[32]  Younglim Lee,et al.  A Primary Acoustic Startle Pathway: Obligatory Role of Cochlear Root Neurons and the Nucleus Reticularis Pontis Caudalis , 1996, The Journal of Neuroscience.

[33]  C. Kros,et al.  Developmental expression of the potassium current IK,n contributes to maturation of mouse outer hair cells , 1999, The Journal of physiology.

[34]  R. Petralia,et al.  Variations in the tangential distribution of postsynaptic glutamate receptors in Purkinje cell parallel and climbing fiber synapses during development , 1998, Neuropharmacology.

[35]  P. Schwartzkroin,et al.  Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[36]  M. Sanders Handbook of Sensory Physiology , 1975 .

[37]  Jean K. Moore,et al.  Nigrotectal projection to the inferior colliculus: Horseradish peroxidase transport and tyrosine hydroxylase immunohistochemical studies in rats, cats, and bats , 1989, The Journal of comparative neurology.

[38]  R. Eatock,et al.  Postnatal Development of Type I and Type II Hair Cells in the Mouse Utricle: Acquisition of Voltage-Gated Conductances and Differentiated Morphology , 1998, The Journal of Neuroscience.