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J Physiol 582.3 (2007) pp 901–902 901
EDITORIAL
Regulation of ion channelsand transporters byphosphatidylinositol4,5-bisphosphate
Brian Robertson
Institute of Membrane and Systems Biology,
Faculty of Biological Sciences, University of
Leeds, Leeds LS2 9NQ, UK
Email: [email protected]
Phosphatidylinositol-4,5-bisphosphate, or
more prosaically, PIP2, doesn’t exactly roll
off the tongue does it? But who would
have thought such a dreary sounding
molecule, a mere lipid at that, could
provide such an interesting and powerful
regulator of key signalling molecules? For
someone weaned on the famous Singer
and Nicholson cartoon, where the crucial
proteins such as ion channels and receptors
floated in a sea of otherwise rather
dull supporting cast lipids, the following
Journal of Physiology symposium proved
fascinating and revelatory. The symposium
‘Regulation of ion channels and transporters
by phosphatidylinositol 4,5-bisphosphate
(PIP2)’, held in conjunction with the 51st
Biophysical Society Annual Meeting in
Baltimore, proved a great success, with
most of the great and the good in the
PIP2 field presenting outstanding semi-
nars, which have become reports of current
theories and cutting-edge developments in
this issue of The Journal of Physiology. The
only thing lacking is the stimulating and
often colourful discussions and questions
and answers, but these reports will provide
the reader with a most valuable introduction
to this fascinating field.
Don Hilgeman (2007) reminds us how
he and his colleagues were the first to
observe roles for PIP2 on ion channels
and exchangers aside from its canonical
function in phosphoinositide signalling
(where it is a precursor for DAG and
IP3). He discovered that PIP2 modulated
Kir channels and Na+/Ca2+ exchangers
in cardiac muscle, and in his present
report shows that the membrane surface
availability of PIP2 acts in a permissive
manner, allowing these signalling and trans-
port proteins to be active, whilst the absence
of PIP2 in intracellular membranes keeps
these channels ‘sleeping’ whilst they are
being trafficked or processed deep inside
the cell. His review also deals with inter-
esting experiments on internalization and
potential compartmentalization of PIP2 in
cellular membranes (the latter being a
recurring theme throughout the meeting).
Bertil Hille, as always, provided an
authoritative review of his group’s
tremendous efforts in unravelling the
regulation of voltage-gated KCNQ/Kv7
channels (some of which underlie the
famous ‘M’ current – see below) by
PIP2. Suh & Hille (2007) review some
of the recent elegant experiments using
sophisticated optical probes and kinetic
modelling showing how dynamic changes
in PIP2 concentration can control M current
amplitude in model cells transfected with
KCNQ2 and KCNQ3 channel subunits. This
work was nicely echoed and extended by
David Brown, who as the Godfather of the
M current, provided a magisterial review of
the regulation of M current in neurons by
PIP2 (Brown et al. 2007). Once again, using
a variety of techniques, including the new
powerful optical probes, he compared and
contrasted the actions of bradykinin and
oxotremorine (a standard mAchR agonist)
on sympathetic ganglion cells, showing
how distinct signalling pathways involving
PIP2 as a master regulator allow neurones
to subtly alter their overall output. The
ever-increasing subtleties in modulation of
neurotransmission serve to remind us, like
J. B. S. Haldane’s conjecture, that neuronal
signalling after agonist binding is not only
more complex than we suppose but perhaps
more complicated than we can suppose!
Some of the difficulties in testing
hypotheses about PIP2 action have been
overcome with tools developed by Tobias
Meyer and Tamas Balla. Here, Balla (2007)
comprehensively illuminates his group’s
progress in developing optical probes
(with different phosphoinositide binding
domains fused to fluorescent indicators)
including a ‘new generation’ of PIP2 tools
– inducible regulators of PIP2 turnover – to
dissect out PIP2’s functional roles and to
alter PIP2 concentration inside cells.
The report of Voets & Nilius (2007) focuses
on modulation of the highly fashionable
TRP channels, a class of membrane protein
which appears to be affected by a new
chemical entity or physical force almost
weekly. In particular, they home in on
the dramatic modulation of the TRPM4
channel’s voltage and calcium dependence
by PIP2 – the former seeing a leftward shift
in V 1/2 to more physiological voltages and
the latter having an almost 100-fold increase
in apparent affinity.
Leslie Loew gave a beautifully illustrated
talk entitled ‘Where does all the PIP2 come
from?’ (Loew, 2007) in which he uses the
‘Virtual Cell’ portal, an online facility run
at the University of Connecticut Health
Center (where he is also Director), which
provides a computational modelling and
simulation problem solving environment
for cell biology. Loew used this powerful
tool to model kinetics of PIP2 breakdown
and release of its metabolites, to test existing
models and propose further experiments, to
help us to better understand what is really
going on with phosphoinositide turnover
when one particular reaction in the cycle,
for example, PLC-induced PIP2 hydrolysis,
is up-regulated.
Using powerful molecular modelling,
with mapping of PIP2 onto the
three-dimensional atomic scale models of
Kir channels, Diomedes Logothetis gave a
beautiful and compelling presentation. The
report here shows some of these models,
which also gives data from his group’s
site-directed mutagenesis experiments,
resulting in a more than plausible scheme
which can explain channel activation by
PIP2 (Logothetis et al. 2007). Furthermore,
because of the proximity of the PIP2 binding
site to those sites of action of a variety of
modulators, Logothetis et al. convincingly
argue the hypothesis that PIP2 might serve
as a merging point for multiple modulatory
pathways.
Mark Shapiro gave a stimulating
and informative talk on ‘Regulation
of voltage-gated Ca2+ channels by
phosphoinositides’, which outlined his
and his colleagues’ recent efforts in
deciphering the control of N and P/Q
type calcium channels by different Gq/11
coupled receptors. In their present review,
Gamper & Shapiro (2007) take the
opportunity to expand upon that theme,
discussing more generally how cellular and
receptor specificity might be achieved with
PIP2 signalling – for instance, are there
membrane microdomains? Importantly,
they also point out that all of those fabulous
indicators (such as GFP-tagged plekstrin
homology domains) currently employed
in this expanding field may bring their
C© 2007 The Author. Journal compilation C© 2007 The Physiological Society DOI: 10.1113/jphysiol.2007.138412
902 Editorial J Physiol 582.3
own problems to the measurement of
PIP2, since by their very nature they can
change the concentration of PIP2 in tiny
enclosed regions – leading to a sort of
‘Uncertainty PIPrinciple’. Luckily, they
point out that a broad based approach to
unravel the complexities of PIP2 signalling
will be required, perhaps necessitating
another such high-quality symposium and
symposium proceedings in the near future.
For my own part, I had great expectations of
this PIP meeting (a joke which died betwixt
my lips and several score biophysicists ears),
which thanks to the excellent speakers and
the expert Chairs, Gamper and Shapiro,
were well exceeded. Thank you to all, and
I hope the readers enjoy some of the results.
The interested reader is also encouraged
to read the following research papers on
the fascinating and growing physiology
of PIP2, which are also published in the
present volume (Crowder et al. 2007; Nam
et al. 2007; Nielsen et al. 2007; Shen et al.
2007; Sohn et al. 2007; Yaradanakul et al.
2007).
References
Balla T (2007). Imaging and manipulating
phosphoinositides in living cells. J Physiol
582, 927–937.
Brown DA, Hughes SA, Marsh SJ & Tinker A
(2007). Regulation of M(Kv7.2/7.3) channels
in neurons by PIP2 and products of PIP2
hydrolysis: significance for receptor-mediated
inhibition. J Physiol 582, 917–925.
Crowder EA, Saha MS, Pace RW, Zhang H,
Prestwich GD & Del Negro CA (2007).
Phosphatidylinositol 4,5-bisphosphate
regulates inspiratory burst activity in the
neonatal mouse preBotzinger complex.
J Physiol 582, 1047–1058.
Gamper N & Shapiro MS (2007). Target-specific
PIP2 signalling: how might it work? J Physiol
582, 967–975.
Hilgemann DW (2007). On the physiological
roles of PIP2 at cardiac Na+–Ca2+ exchangers
and KATP channels: a long journey from
membrane biophysics into cell biology.
J Physiol 582, 903–909.
Loew LM (2007). Where does all the PIP2 come
from? J Physiol 582, 945–951.
Logothetis DE, Lupyan D & Rosenhouse-
Dantsker A (2007). Diverse Diverse Kir
modulators act in close proximity to residues
implicated in phosphoinositide binding.
J Physiol 582, 953–965.
Nam JH Lee H-S, Nguyen YH, Kang TM, Lee
SW, Kim H-Y, Kim SJ, Earm YE & Kim SJ
(2007). Mechanosensitive activation of K+channel via phospholipase C-induced
depletion of phosphatidylinositol
4,5-bisphosphate in B lymphocytes. J Physiol
582, 977–990.
Nielsen DK, Jensen AK, Harbak H, Christensen
SC & Simonsen LO (2007). Cell content of
phosphatidylinositol (4,5)bisphosphate in
Ehrlich mouse ascites tumour cells in response
to cell volume perturbations in anisotonic
and in isosmotic media. J Physiol 582,
1027–1036.
Shen C, Lin M-J, Yaradanakul A, Lariccia V, Hill
JA & Hilgemann DW (2007). Dual control of
cardiac Na+-Ca2+ exchange by PIP2: analysis
of the surface membrane fraction by
extracellular cysteine PEGylation. J Physiol
582, 1011–1026.
Sohn J-W, Lim A, Lee S-H & Ho W-K (2007).
Decrease in PIP2–channel interactions is the
final common mechanism involved in PKC-
and arachidonic acid-mediated inhibitions of
GABAB-activated K+ current. J Physiol 582,
1037–1046.
Suh B-C & Hille B (2007). Regulation of
KCNQ channels by manipulation of
phosphoinositides. J Physiol 582,
911–916.
Voets T & Nilius B (2007). Modulation of TRPs
by PIPs. J Physiol 582, 939–944.
Yaradanakul A, Feng S, Shen C, Lariccia V,
Lin M-J, Yang J, Kang TM, Dong P,
Yin HL, Albanesi JP & Hilgemann DW
(2007). Dual control of cardiac Na+–Ca2+exchange by PIP2: electrophysiological
analysis of direct and indirect mechanisms.
J Physiol 582, 991–1010.
C© 2007 The Author. Journal compilation C© 2007 The Physiological Society