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: b.robertson@leeds.ac.uk

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