phoradixin beginning at the ganglioside-PI(4,5)P
only there should PI(4,5)P
be present at high enough levels to
preactivate radixin, allowing activating phosphorylation by an
unknown kinase. Indeed, the phosphoradixin profile seen in
bundles can be modeled accurately as the [pRDX] ⫽ [RDX]
A), suggesting that phosphoradixin forma-
tion depends steeply on the concentrations of radixin and
. Moreover, the presence of ceramide in the taper do
main could also promote radixin dephosphorylation, as is the
case for ezrin (Canals et al., 2010). This phosphoradixin activa-
tion zone recalls the concentration of phospho-ERM proteins
toward microvillar tips, despite the presence of total ERM pro-
teins throughout a microvillus (Hanono et al., 2006).
Based on recruitment of the PDZ-domain protein SLC9A3R1
by ERM proteins in microvilli (Reczek et al., 1997), once stereo-
cilia radixin is activated, we speculate that it recruits the paralog
SLC9A3R2, which is present at a concentration close to that of
radixin (J.-B. Shin and P. G. Gillespie, unpublished observa-
tions). SLC9A3R2, in turn, may bind to many important stereo-
cilia proteins (J.-B. Shin and P. G. Gillespie, unpublished
observations). In addition, as in other systems (Fehon et al.,
2010), activated radixin may bind directly to other membrane
proteins, serving as a actin-membrane connector. The role of
ERM proteins is so important that in radixin’s absence, hair cells
upregulate the paralog ezrin, partially compensating for radixin’s
loss (Kitajiri et al., 2004).
The bundle contains far more PTPRQ, which degrades PI(4,5)P
than it does the PI(4,5)P
synthetic enzymes PIK4CA, PIP5K2B,
and PIP5K1A. While turnover numbers for these enzymes are not
known, if PI(4,5)P
freely interacted with PTPRQ, present at a
concentration ⬎100-fold greater than the synthetic enzymes, it
would be readily hydrolyzed. The glycosphingolipid domain may
therefore act as a physical barrier to prevent PI(4,5)P
between the hair bundle and apical surface; PI(4,5)P
the domain infrequently because of structural mismatch with
glycosphingolipid domain, but PTPRQ would be present to mop
up those PI(4,5)P
molecules that did manage to penetrate the
basal taper compartment.
Are there reasons for compartmentalization of PI(4,5)P
stereocilia beyond phosphoradixin activation? PI(4,5)P
the apical surface may fluctuate as exocytosis occurs, as fusion of
vesicles with the plasma membrane is associated with PI(4,5)P
synthesis. In contrast, PI(4,5)P
controls transduction and adap
tation (Hirono et al., 2004), as well as other critical molecules
such as PMCA2. Formation of a discrete stereocilia PI(4,5)P
domain using the glycosphingolipid physical barrier thus allows
precise activity control through PI(4,5)P
Gangliosides play an essential role in the inner ear; mice with
a null mutation in GM3 synthase, which is essential for formation
of most ganglioside species, transiently show some responses in
an auditory brainstem response assay; however, all knockout
mice are deaf by postnatal day 17 (Yoshikawa et al., 2009). The
ganglioside defect could be in stereocilia; likewise, PTPRQ null
mice show progressive hearing loss that is complete by several
weeks of age (Goodyear et al., 2003). We thus suggest that the
basal taper domain, consisting of glycosphingolipids and PTPRQ
(Fig. 8 B), is essential for hair-cell function, presumably by segre-
, PMCA2, and other stereocilia components
away from the soma’s apical surface and allowing radixin activa-
tion in a spatially precise manner.
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