Biomedical subjects

David P Corey

Publications and source records attributed to David P Corey.

7 recordsLinked to original sources

PubMed2003

New TRP channels in hearing and mechanosensation.

Despite extensive biophysical characterization and the superb example of the bacterial MscL channel, molecular identification of eukaryotic mechanosensitive channels has been slow. New members of the TRP superfamily have emerged as candidate channels to mediate touch, hearing, fluid flow, and osmosensation in sensory and nonsensory cells. Distinguishing between direct mechanical activation and indirect second messenger activation is still a challenge.

Animals↗

PubMed2003

Lighting up the senses: FM1-43 loading of sensory cells through nonselective ion channels.

We describe a novel mechanism for vital fluorescent dye entry into sensory cells and neurons: permeation through ion channels. In addition to the slow conventional uptake of styryl dyes by endocytosis, small styryl dyes such as FM1-43 rapidly and specifically label hair cells in the inner ear by entering through open mechanotransduction channels. This labeling can be blocked by pharmacological or mechanical closing of the channels. This phenomenon is not limited to hair cell transduction channels, because human embryonic kidney 293T cells expressing the vanilloid receptor (TRPV1) or a purinergic receptor (P2X2) rapidly take up FM1-43 when those receptor channels are opened and not when they are pharmacologically blocked. This channel permeation mechanism can also be used to label many sensory cell types in vivo. A single subcutaneous injection of FM1-43 (3 mg/kg body weight) in mice brightly labels hair cells, Merkel cells, muscle spindles, taste buds, enteric neurons, and primary sensory neurons within the cranial and dorsal root ganglia, persisting for several weeks. The pattern of labeling is specific; nonsensory cells and neurons remain unlabeled. The labeling of the sensory neurons requires dye entry through the sensory terminal, consistent with permeation through the sensory channels. This suggests that organic cationic dyes are able to pass through a number of different sensory channels. The bright and specific labeling with styryl dyes provides a novel way to study sensory cells and neurons in vivo and in vitro, and it offers new opportunities for visually assaying sensory channel function.

Animals↗

PubMed2002

Understanding inner ear development with gene expression profiling.

Understanding the development of the inner ear requires knowing the spatial and temporal pattern of gene expression, and the functions of those gene products. In the last decade, hearing research has benefited tremendously from the progress of the human and mouse genome projects, as amply illustrated by the identification of many deafness genes in both human and mouse. However, the sheer amount of information generated from the genome project has far outpaced the rate at which it is utilized. Microarray technology offers a means to quantify the expression level of transcripts at a whole-genome scale. Cross-tissue comparisons will identify genes unique to the inner ear, which will expedite the identification of new deafness genes. Microdissection and subtraction after ablation of cell types can reveal genes expressed in certain cells, such as hair cells. Expression profiling of both inner ear and other tissues, under a variety of conditions (such as during development, with drug treatment or in knock-out animals), can be used for cluster analysis to group genes of similar expression. Coexpression can suggest functional pathways and interactions between known genes, and can identify new genes in a structure or pathway. In this review we give examples for both transcription factors and cochlear structures.

Animals↗

PubMed2002

Vascular defects and sensorineural deafness in a mouse model of Norrie disease.

Norrie disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature.

Acoustic Stimulation↗

PubMed2002

A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells.

Myosin-1c (also known as myosin-Ibeta) has been proposed to mediate the slow component of adaptation by hair cells, the sensory cells of the inner ear. To test this hypothesis, we mutated tyrosine-61 of myosin-1c to glycine, conferring susceptibility to inhibition by N(6)-modified ADP analogs. We expressed the mutant myosin-1c in utricular hair cells of transgenic mice, delivered an ADP analog through a whole-cell recording pipette, and found that the analog rapidly blocked adaptation to positive and negative deflections in transgenic cells but not in wild-type cells. The speed and specificity of inhibition suggests that myosin-1c participates in adaptation in hair cells.

Adenosine Diphosphate↗

PubMed2002

An inner ear gene expression database.

Microarray technology has provided an unprecedented opportunity to study gene expression profiles at a whole-genome level. As a first step toward a comprehensive understanding of inner ear gene expression, mouse cochleas were examined at two developmental stages (P2 and P32) using GeneChip oligonucleotide arrays. A large number of genes and ESTs (> 10,000) were found to be expressed in the cochlea. Expression profiles derived from duplicate samples at the same developmental stages showed general agreement and indicated the reproducibility of the assay. The expression of many known hair-cell genes was detected in the whole-cochlea samples, demonstrating the relatively high sensitivity of the assay. Genes highly expressed only at P2 or P32 were also identified and their expression patterns correlate with their functions in the cochlea. A web-based database with external links was set up for public access, which should facilitate the discovery of genes important in the development and function of the inner ear and should aid the identification of additional deafness genes.

Animals↗

PubMed2001

The PDZ domain protein PICK1 and the sodium channel BNaC1 interact and localize at mechanosensory terminals of dorsal root ganglion neurons and dendrites of central neurons.

Members of the BNaC/ASIC family of ion channels have been implicated in mechanotransduction and nociception mediated by dorsal root ganglion (DRG) neurons. These ion channels are also expressed in the CNS. We identified the PDZ domain protein PICK1 as an interactor of BNaC1(ASIC2) in a yeast two-hybrid screen. We show by two-hybrid assays, glutathione S-transferase pull-down assays, and coimmunoprecipitations that the BNaC1-PICK1 interaction is specific, and that coexpression of both proteins leads to their clustering in intracellular compartments. The interaction between BNaC1 and PICK1 requires the PDZ domain of PICK1 and the last four amino acids of BNaC1. BNaC1 is similar to two other BNaC/ASIC family members, BNaC2 (ASIC1) and ASIC4, at its extreme C terminus, and we show that PICK1 also interacts with BNaC2. We found that PICK1, like BNaC1 and BNaC2, is expressed by DRG neurons and, like the BNaC1alpha isoform, is present at their peripheral mechanosensory endings. Both PICK1 and BNaC1alpha are also coexpressed by some pyramidal neurons of the cortex, by pyramidal neurons of the CA3 region of hippocampus, and by cerebellar Purkinje neurons, localizing to their dendrites and cell bodies. Therefore, PICK1 interacts with BNaC/ASIC channels and may regulate their subcellular distribution or function in both peripheral and central neurons.

Acid Sensing Ion Channels↗