The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration
| Autor: | Keiichi Nagata, Andrew J. Castiglioni, Jaime García-Añoveros, Thomas Madathany, Lili Zheng, James R. Bartles |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Proline
Stereocilia (inner ear) TRPM Cation Channels Gadolinium Biology Models Biological Epithelium Cell Line Mice Transient receptor potential channel Transient Receptor Potential Channels Hair Cells Auditory otorhinolaryngologic diseases medicine Animals Humans Inner ear Alleles Ion channel Vestibular system Alanine Multidisciplinary Anatomy Biological Sciences Cell biology Electrophysiology medicine.anatomical_structure Microscopy Fluorescence Cell culture Mutation sense organs Hair cell |
| Zdroj: | Proceedings of the National Academy of Sciences. 105:353-358 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Varitint-waddler (Va and Va J ) mice are deaf and have vestibular impairment, with inner ear defects that include the degeneration and loss of sensory hair cells. The semidominant Va mutation results in an alanine-to-proline substitution at residue 419 (A419P) of the presumed ion channel TRPML3. Another allele, Va J , has the A419P mutation in addition to an I362T mutation. We found that hair cells, marginal cells of stria vascularis, and other cells lining the cochlear and vestibular endolymphatic compartments express TRPML3. When heterologously expressed in LLC-PK1-CL4 epithelial cells, a culture model for hair cells, TRPML3 accumulated in lysosomes and in espin-enlarged microvilli that resemble stereocilia. We also demonstrated that wild-type TRPML3 forms channels that are blocked by Gd 3+ , have a conductance of 50–70 pS and, like many other TRP channels, open at very positive potentials and thus rectify outwardly. In addition to this outward current, TRPML3(419P) and (I362T+A419P) generated a constitutive inwardly rectifying current that suggests a sensitivity to hyperpolarizing negative potentials and that depolarized the cells. Cells expressing TRPML3(A419P) or (I362T+A419P), but not wild-type TRPML3, died and were extruded from the epithelium in a manner reminiscent of degenerating hair cells in Va mice. The increased open probability of TRPML3(A419P) and (I362T+A419P) at physiological potentials likely underlies hair cell degeneration and deafness in Va and Va J mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|