PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Abstract
Ca2! enters the stereocilia of hair cells through mechanoelectrical
transduction channels opened by the deflection of the hair bundle
and is exported back to endolymph by an unusual splicing isoform
(w/a) of plasma-membrane calcium-pump isoform 2 (PMCA2).
Ablation or missense mutations of the pump cause deafness, as
described for the G283S mutation in the deafwaddler (dfw) mouse.
A deafness-inducing missense mutation of PMCA2 (G293S) has
been identified in a human family. The family also was screened for
mutations in cadherin 23, which accentuated hearing loss in a
previously described human family with a PMCA2 mutation. A
T1999S substitution was detected in the cadherin 23 gene of the
healthy father and affected son but not in that of the unaffected
mother, who presented instead the PMCA2 mutation. The w/a
isoform was overexpressed in CHO cells. At variance with the other
PMCA2 isoforms, it became activated only marginally when exposed
to a Ca2! pulse. The G293S and G283S mutations delayed the
dissipation of Ca2! transients induced in CHO cells by InsP3. In
organotypic cultures, Ca2! imaging of vestibular hair cells showed
that the dissipation of stereociliary Ca2! transients induced by Ca2!
uncaging was compromised in the dfw and PMCA2 knockout mice,
as was the sensitivity of the mechanoelectrical transduction channels
to hair bundle displacement in cochlear hair cells.
hereditary hearing loss " mutations " calcium homeostasis "
calcium transport
