8 | JANUARY 2005 | VOLUME 6 www.nature.com/reviews/neuro
R E S E A R C H H I G H L I G H T S
New results published in Nature
show that songbirds can accomplish
remarkable feats of learning, at least
when it comes to learning to sing.
Rather like sequencing a genome by
shotgun sequencing -- splitting the
genome into fragments that can be
easily sequenced and then put back in
the right order -- white-crowned
sparrows can learn their songs in
pieces.
Shotgun sequencing requires a
computer to reassemble the short
sequences into the correct order by
matching overlapping segments.
Rose et al. show that white-crowned
sparrows are capable of a similar feat
when it comes to learning their song:
after being exposed only to short but
overlapping snippets of a`tutor song',
the young songbirds can reproduce
the full tune. Beyond the remarkable
animal behaviour story, the results
offer insight into how the brain
might store auditory memories that
guide learned vocal behaviour.
The authors collected nestlings
and exposed them to a recorded tutor
song from the age of about 10 days.
The researchers deliberately frag-
mented the recordings,so instead of a
usual white-crowned song -- which
consists of four or five ordered
`phrases'of whistles,trills,buzzes and
so on -- the young birds listened to
pairs of normally adjacent phrases.
For example, if a full song consists of
ABCDE (with each letter representing
a phrase),the birds might have heard
DE,CD,BC andAB,with silent inter-
vals separating the phrase pairs.
Rose et al.found that birds tutored
on only adjacent phrase pairs could
produce a normal,correctly ordered
song,akin to singing`Mary had a little
lamb'correctly after only having ever
heard`little lamb'`a little'`had a'and
`Mary had'.Furthermore,in a separate
experiment in which birds were
tutored with reverse-order syllables
(BA,CB,etc.) the birds learned to sing
a fully reversed song (EDCBA).This
latter result is even more remarkable
in light of previous evidence that
white-crownedsparrowshaveastrong
innate tendency -- even in the
absence of any tutor -- to start songs
with`A-like'introductory phrases.The
authors confirmed that the overlap-
ping phrase-pairs were essential, as
birds that only heard single phrases --
even though they heard all the phrases
--couldnotsingnormalsongs.
Mechanosensitive ion channels convert
external mechanical forces into electrical and
chemical signals in the cell.In the case of the
TREK-1 channel,it is opened by membrane
stretch and cell swelling,which results in
outward rectifying potassium currents and
shaping of the action potential.Reporting in
the EMBOJournal,Chemin and colleagues
found that phospholipids are important in
this mechanical gating process.
An artificial increase in the cytosolic
concentration of phosphatidylinositol
4,5-bisphosphate (PIP2
) -- a component of
membrane phospholipids -- stimulates the
activity of endogenous TREK-1 in cultured
striatal neurons.This elevation in channel
activity is also seen when the cytosol is
acidified,and the effects of both PIP2
and low
intracellular pH can be inhibited by the
presence of positively charged intracellular
molecules such as polylysine.The inhibitory
effect of polylysine molecules is thought to be
due to their interaction with the negative
charges of membrane phospholipids,which
prevents them from interacting
electrostatically with specific positively
charged segments in the channel protein.
The authors also show that PIP2
and acid can
regulate the gating of TREK-1 in a cooperative
manner:when TREK-1 is challenged with acid
after addition of PIP2
,it becomes`locked'in a
highly active form even after the cytosolic pH
is returned to pH 7.2.The activity of the
locked TREK-1 channel is high even at
atmospheric pressure,and pressure
stimulation produces only a modest further
activating effect.TREK-1 activation becomes
more resistant to membrane stretch in the
presence of polylysine,which indicates that
the cationic molecule interferes with the
pressure-sensing process.
Which segment of the channel is responsible
for PIP2
stimulation? The authors generated
truncated,chimaeric and point mutations in
TREK-1,and analysed the channel activity in
cells that overexpressed the mutant proteins.
They found that a protein segment of the
cytosolic carboxy-terminal domain of TREK-1
is crucial for PIP2
stimulation.This region
contains several positively charged resides that
seem to be attractive candidates for binding to
phospholipids.A systematic substitution of
the positively charged amino acids by
alanines,which are neutral,progressively leads
to reduced TREK-1 stimulation by PIP2
.The
authors conclude that the cationic cluster is
important for stimulation of TREK-1 by
phospholipids.
Chemin and colleagues then reasoned that
if this positively charged region of TREK-1 is
to interact with phospholipids, it must be
localized near the plasma membrane. To
show this, they used a complementation
yeast system, in which a mutant strain fails
to grow at the non-permissive temperature
of 37 o
C unless it is rescued by the
exogenously expressed amino-terminal
fragment of hSOS, which lacks the
membrane-targeting activity.As this
fragment of hSOS is only functional when it
gets to the plasma membrane, mutant yeast
cells are not rescued unless hSOS is fused to
another protein or protein segment that
interacts with the plasma membrane. The
authors show that the cytosolic cationic
cluster of TREK-1 brought the hSOS
fragment to the plasma membrane and
allowed cell growth at 37 o
C.
These findings have shed new light on the
gating mechanism of the TREK channels,
and might also have more general
implications for other types of mechanically
activated ion channel, as Hirono and
colleagues recently suggested for the hair cell
channel.
JaneQiu
References and links
ORIGINAL RESEARCH PAPER Chemin, J. et al. A
phospholipid sensor controls mechanogating of the K+
channel TREK-1. EMBO J. 2 December 2004
(10.1038/sj.emboj.7600494)
FURTHER READING Hirono. M. et al. Hair cells require
phosphatidylinosital 4,5-bisphosphate for mechanical
transduction and adaption. Neuron 44, 309­320 (2004)
Sensing the pressure
ION CHA N N E LS
Stitching together a song memory
B E HAVIOU R
Photograph of a white-crowned
sparrow, courtesy of F. Goller,
University of Utah, USA.