of downstream signalling. However,
Sanada and Tsai found that a GPCR-
independent activator of G proteins,
AGS3, was important for establish-
ing the axis of division in cortical
progenitors. AGS3 is expressed by
cortical progenitors in mouse
embryos, and silencing its expression
causes abnormalities in the mitotic
spindle orientation that are similar
to those caused by disruption of G
signalling.
This elegant study provides
the first direct evidence for the
molecular mechanism that regulates
mitotic spindle orientation in corti-
cal progenitor cells. It will lead to
new ways of deciphering the com-
plex events that trigger changes in
cell-cleavage plane orientation and
asymmetric cell fate choices during
neurogenesis.
Jane Qiu
References and links
ORIGINAL RESEARCH PAPER Sanada, K. &
Tsai, L.-H. G protein  subunits and AGS3 control
spindle orientation and asymmetric cell fate of
cerebral cortical progenitors. Cell 122, 119­131
(2005)
FURTHER READING Götz, M. & Huttner, W. B.
The cell biology of neurogenesis. Nature Rev. Mol.
Cell Biol. (in the press)
WEB SITE
Tsai's laboratory: http://www.hms.harvard.edu/
dms/bbs/fac/tsai.html
Ourknowledgeofthestructureofvoltage-dependent
K+
(Kv) channels, which shape the neuronal action
potential, has come largely from studies of prokary-
otic channels, which can be expressed at high levels
in Escherichia coli. Now the crystal structure of a
mammalian Kv channel has been published, pro-
viding important insights into how the structural
features of these channels allow them to operate in
eukaryotic cells.
Eukaryotic Kv channels are very similar to their
prokaryotic counterparts. For example, the sequence
of the selectivity filter -- the part of the channel that
confers specificity for K+
-- is highly conserved and
is likely to produce a similar structure in all K+
chan-
nels. But eukaryotic channels also have some unique
features. To gain a better understanding of the struc-
tural basis of Kv channel function in eukaryotes,
the researchers, led by Rod MacKinnon, chose to
investigate Kv1.2, a member of the Shaker family
of K+
channels.
To obtain crystals of Kv1.2 in its native arrange-
ment, the group used a mixture of lipids and
detergent during purification and crystallization.
This clever approach helped to compensate for
removal of the lipid membrane during isolation
of the channel, keeping the voltage sensors cor-
rectly positioned with respect to the channel pore.
The channel was crystallized in a complex with an
oxidoreductase -subunit, an auxiliary protein that
might regulate mammalian Kv channels in their
natural environment.
The amino terminus of Kv1.2 is known to form a
`T1' domain inside the cell, which is located over the
pore entrance to the cytoplasm. This domain serves
as a binding site for the -subunit, which is thought
to be involved in the process of channel inactivation.
Long et al. found that the relationships between
the membrane-spanning components of Kv1.2, the
intracellular T1 domain and the -subunit were
consistent with functional studies of inactivation
gating in Shaker channels. Interestingly, the struc-
ture also pointed to a possible role of the -subunit
as a redox sensor, coupling the redox state of the cell
to activity of the channel.
Kv1.2 was crystallized with the pore in the open
conformation. Because the normal conformation
of the voltage sensors was preserved in this struc-
ture, Long et al. were able to take a closer look
at the way in which the voltage sensor `paddles',
which move through the membrane in response
to voltage changes, open and close the pore. They
found that the voltage sensors are almost inde-
pendent domains inside the membrane, being
only weakly attached to the pore through `linker'
helices. The positioning of arginine residues in the
voltage sensor suggested that a balance between
electrostatic and hydrophobic forces is central to
the way in which the sensor performs mechanical
work on the pore.
The hope is that these fascinating insights into
the structure of a mammalian Kv channel in the
open conformation will soon be followed by a view
of the switch in its closed state.
Rebecca Craven
References and links
ORIGINAL RESEARCH PAPERS Long, S. B. et al. Crystal structure of
a mammalian voltage-dependent Shaker family K+
channel. Science
7 July 2005 (doi:10.1126/science.1116269) | Long, S. B. et al. Voltage
sensor of Kv1.2: structural basis of electromechanical coupling.
Science 7 July 2005 (doi:10.1126/science.1116270)
FURTHER READING Jiang, Y. et al. X-ray structure of a voltage-
dependent K+
channel. Nature 423, 33­41 (2003) | Swartz, K. J.
Towards a structural view of gating in potassium channels. Nature Rev.
Neurosci. 5, 905­916 (2004)
ION CHA N N E L STRUCTU R E
Switching on to potassium channels
NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | SEPTEMBER 2005 | 667
R E S E A R C H H I G H L I G H T S