Cell and Molecular Biology of TRP Channels
Regulation of calcium signalling by adenine-based
second messengers
R. Fliegert, A. Gasser and A.H. Guse1
The Calcium Signalling Group, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Centre of Experimental Medicine,
University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
Abstract
cADPR [cyclic ADPR (ADP-ribose)], NAADP (nicotinic acid–adenine dinucleotide phosphate) and ADPR belong
to the family of adenine-containing second messengers. They are metabolically related and are all involved in
the regulation of cellular Ca2+ homoeostasis. Activation of specific plasma membrane receptors is connected
to cADPR formation in many cell types and tissues. In contrast receptor-mediated formation of NAADP and
ADPR has been shown only in a few selected cellular systems. The intracellular Ca2+ channel triggered by
cADPR is the RyR (ryanodine receptor); in the case of NAADP, both activation of RyR and a novel Ca2+
channel have been proposed. In contrast, ADPR opens the non-specific cation channel TRPM2 [TRP (transient
receptor potential) melastatin 2] that belongs to the TRP family of ion channels.
Adenine-based second messengers
The first second messenger discovered in 1957 was cAMP
[1]. This cyclic adenine-containing nucleotide has since been
shown to mediate important intracellular effects, including
activation of glycogenolysis in hepatocytes and mobilization
of fatty acids in adipose tissue. However, except in cardiac
myocytes, cAMP is not connected to increases in [Ca2+ ]i
(cytosolic free Ca2+ concentration). On the other hand
changes in [Ca2+ ]i have been early recognized as one of the
most important, powerful and versatile mechanisms of
intracellular signal transduction since such changes occur in
response to many extracellular signals, e.g. hormones, mediators, cell–cell contacts or physical stimuli in many different cells and organisms. Accordingly, research has focused
on putative second messengers regulating rapid movements of Ca2+ ions across the membranes of intracellular
Ca2+ stores, e.g. the ER (endoplasmic reticulum)/SR (sarcoplasmic reticulum), or across the plasma membrane. These
rapid directed movements of Ca2+ ions are possible since
SERCAs (SR/ER Ca2+ -ATPases) or PMCAs (plasmamembrane Ca2+ -ATPases) continuously build up significant
gradients by pumping Ca2+ ions into the stores or into the
extracellular space.
In 1983, Schulz and Berridge discovered that InsP3 releases
Ca2+ from the ER [2]. InsP3 has since then been shown to be
involved in the generation of both local and global Ca2+ signals in many different cellular signal transduction processes
(reviewed in [3]).
Key words: ADP-ribose (ADPR), cyclic ADP-ribose (cADPR), calcium signalling, nicotinic acid–
adenine dinucleotide phosphate (NAADP), second messenger, transient receptor potential
melastatin 2 (TRPM2).
Abbreviations used: ADPR, ADP-ribose; ADPRC, ADP-ribosyl cyclase; [Ca2+ ]i , cytosolic free Ca2+
concentration; cADPR, cyclic ADPR; CRACM1, Ca2+ release-activated Ca2+ channel modulator 1;
ER, endoplasmic reticulum; NAADP, nicotinic acid–adenine dinucleotide phosphate; N1-cIDPR,
N1-cyclic inosine diphosphoribose; PARP, poly(ADPR) polymerase; RyR, ryanodine receptor; SR,
sarcoplasmic reticulum; TRP, transient receptor potential; TRPM2, TRP melastatin 2.
1
To whom correspondence should be addressed (email [email protected]).
After the discovery of the InsP3 /Ca2+ signalling system, it
came as a surprise that additional small endogenous molecules
are able to release Ca2+ from intracellular stores. In their
pioneering work, Lee and co-workers [4–6] discovered two
such compounds, cADPR [cyclic ADPR (ADP-ribose)]
and NAADP (nicotinic acid–adenine dinucleotide phosphate).
Interestingly, there is a relatively close metabolic relationships between cADPR and NAADP. The main pathway
to cADPR formation proceeds from NAD+ to cADPR
catalysed by ADPRC (ADP-ribosyl cyclase) activity (Figure 1; reviewed in [7]). In addition, it is well known that
NAD+ can be converted into NADP+ by NAD kinase
(Figure 1). NAADP formation by a base-exchange reaction
is then catalysed by ADPRC, the same class of enzymes
that also synthesize cADPR (Figure 1). In addition to the
Ca2+ -releasing second messengers cADPR and NAADP, in
2001 the modulatory activity of a third adenine-containing
nucleotide involved in Ca2+ homoeostasis, ADPR, was
discovered [8,9]. ADPR acts on a non-specific cation channel
of the plasma membrane termed TRPM2 [TRP (transient
receptor potential) melastatin 2].
The cADP-ribose/Ca2+ signalling pathway
In-depth review papers dealing with the cADPR/Ca2+ signalling system have been published in recent years [10–13];
readers interested in additional details or aspects not covered
by the current review may refer to these.
The cADPR/Ca2+ signalling pathway has been detected
in several cell types, including smooth, skeletal and cardiac
muscles, neuronal and neuronal-related cells, haemopoietic
cells, acinar cells and oocytes (for a more complete list refer
to [10]). Activation of ADPRC is induced by ligation of
receptors localized in the plasma membrane (Figure 2) and
leads to increased concentrations of cADPR within the cell.
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Figure 1 Metabolic relationships between the Ca2+ messengers cADPR, ADPR and NAADP
Abbreviations used: NicAmide, nicotinamide; NicAcid, nicotinic acid; NAADP-R, proposed NAADP receptor.
Figure 2 Receptor-mediated formation and sites of action of adenine-based, Ca2+ -modulating second messengers
Dotted lines indicate minor pathways or relationships not generally accepted or proven. NADase, NAD+ glycohydrolase;
NudT9-H, NudT9 homology region.
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Cell and Molecular Biology of TRP Channels
The identity of the mammalian ADPRC forming cADPR
inside cells is still somewhat controversial since the only
molecularly known mammalian ADPRCs, CD38 and CD157
(reviewed in [7]), are ectoenzymes. For CD38, De Flora et al.
[12] have solved this ‘topological paradox’ as depicted in
Figure 2: NAD+ is transported into the extracellular space
via connexin 43. There, it is converted by ecto-CD38 into
cADPR that is directly transported by CD38 or, more likely,
by nucleoside transporters into the cytosol (reviewed in [12]).
Uptake systems for cADPR also open the possibility for
paracrine action of cADPR; indeed, paracrine- and cADPRmediated relationships between several cell systems have been
demonstrated (reviewed in [12]).
Recent work on CD38 revealed the structure of its extracellular domain at high resolution [14]. However, experiments
in tissues from CD38 knockout mice indicate that additional
cADPR-forming enzymatic activities are expressed [15]. Another interesting recent finding relates to novel adenine
nucleotides of the Ap2A-type (adenosine–PPi –adenosine)
formed by ADPRC in the presence of adenine; these compounds interfere with Ca2+ signalling in vitro and display
cytotoxic properties [16].
Once cADPR is formed, it increases [Ca2+ ]i . The most well
known targets for cADPR are RyRs (ryanodine receptors),
one of the principal classes of intracellular, ligand-operated
ion channels. Whether cADPR binds directly to RyR or first
attaches to a soluble binding protein remains to be determined: evidence for a cADPR-binding protein has been presented by photo-affinity labelling studies [17] and by direct
binding of cADPR to FKBP 12.6 (FK506 binding protein
12.6; [18]). Although the molecular identity of the binding
site of cADPR is still unknown, a huge number of derivatives
of cADPR, either synthesized chemically or by chemoenzymatic synthesis, have added significantly to the understanding of its structure–activity relationship. One important
observation was the almost identical biological activity, in
terms of Ca2+ release, of N1-cIDPR (N1-cyclic inosine
diphosphoribose) as compared with cADPR [19]. Derivatives
of N1-cIDPR are also agonists, but with varying potency [20].
Another interesting observation relates to the two ribose moieties connecting the base and the PPi bridge. Zhang and coworkers [21–23] have synthesized derivatives of N1-cIDPR
in which either the ribose connected to N1 of hypoxanthine
(also called ‘northern ribose’) or both ribose moieties have
been replaced by simple diethyl ether or alkane strands. The
diethyl ether and alkane strands partially mimic the ribose,
at least the spacer function between the base and the PPi
bridge. Surprisingly, these derivatives are biologically active
and, owing to their more hydrophobic diethyl ether chains,
are membrane-permeant [21–23].
In addition to Ca2+ release, cADPR appears to be involved
in Ca2+ entry too. In human T-lymphocytes, sustained Ca2+
entry [24] was blocked by the membrane-permeant cADPR
antagonist 7-deaza-8-Br-cADPR and by antisense RNAmediated knock down of type 3 RyR [25]. Furthermore,
application of membrane-permeant agonists to intact cells
induced sustained Ca2+ entry [20–23]. In neutrophils from
wild-type mice the chemotactic peptide fMLP (N-formylmethionyl-leucylphenylalanine; ‘chemotactic peptide’) induced biphasic calcium signalling: calcium release followed by calcium entry [26]. The calcium entry phase was
blocked by the cADPR antagonist, 8-Br-cADPR, and
was absent from neutrophils from Cd38−/− mice. The
Cd38−/− neutrophils lack the ability to produce both cADPR
and ADPR [26], indicating that cADPR and/or ADPR are
essentially involved in neutrophil Ca2+ entry. Two possible
mechanisms exist: on the one hand store depletion by cADPR
may activate capacitative Ca2+ entry (Figure 2). Experiments in DT40 lymphocytes lacking expression of all three
types of InsP3 R suggest activation of a current characteristic of capacitative Ca2+ entry by cADPR [27]. Proteins involved in capacitative Ca2+ entry have been
identified recently as Stim1 and Orai1/CRACM1 (Ca2+
release-activated Ca2+ channel modulator 1) [28,29]. Stim1
is a protein connecting the ER lumen with the putative
Ca2+ channel Orai1/CRACM1 (Figure 2). In addition
to Ca2+ entry via indirect activation of Orai1/CRACM1,
cADPR may also act as co-activator of TRPM2 (see
the section ‘The ADPR/TRPM2/Ca2+ signalling pathway’
below).
The NAADP/Ca2+ signalling pathway
In contrast with cADPR, NAADP has only recently been
accorded full status of a second messenger by demonstrating rapid formation of NAADP in response to certain
extracellular stimuli. Although NAADP had initially been
described as a Ca2+ mobilizing endogenous nucleotide in
1995 [6], it took quite a while for suitable extraction
protocols and quantification methods for NAADP to be
developed. Accurate quantification of the minute amounts of
NAADP in cells is either achieved by a competitive protein
binding assay using a specific NAADP-binding protein
from sea urchin egg [30] or by enzymatic cycling assays
[31,32].
Endogenous basal concentrations of NAADP have been
found to be in the low nanomolar range [30,32,33]. Upon
specific stimulation in pancreatic acinar cells and T-lymphocytes a very rapid and transient increase in NAADP was
observed at approx. 10–30 s post stimulation [30,32]. This
indicates rapid regulation of an NAADP-synthesizing and an
NAADP-metabolizing enzyme (Figure 2). The only known
enzyme to synthesize NAADP is the ectoenzyme CD38;
however, it is unclear how the enzymatic activity of CD38 is
regulated. Thus the question as to which enzymes are involved in the fast metabolism of NAADP remains open.
In T-cells, besides the rapid formation, a sustained increase in
cellular NAADP was observed [32], indicating also a role
in the sustained Ca2+ signalling phase.
The target organelle and the target receptor/Ca2+ channel
for NAADP are also a matter of debate (Figure 2). Data originally obtained in sea urchin eggs indicate that the target
organelle for NAADP is an acidic, lysosome-related compartment [34]. This has been confirmed in some mammalian
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Figure 3 Cellular pathways leading to generation of ADPR and subsequent activation of TRPM2
Schematic presentation of TRPM2 regulation by ADPR, cADPR, NAADP and H2 O2 . Also shown are various potential pathways
of ADPR formation within the cell. Dotted lines indicate minor pathways or relationships not generally accepted or proven.
NT, nucleoside transporter; PARG, poly(ADPR) glycohydrolase; [ADPR]n , poly ADP-ribosyl residues; mito, mitochondrion.
cell types, but other investigators found, at least in addition to
a lysosomal store, also sensitivity of the ER towards NAADP
[35]. Regarding the NAADP receptor/Ca2+ channel, there is
clear pharmacological evidence from the sea urchin egg system that inhibitors of RyR do not block the effect of NAADP
[6]. Ongoing attempts to purify the receptor resulted in its
partial characterization on the biochemical level, but not
in its molecular identification. On the other hand, several
authors have shown for mammalian cells that the Ca2+
channel involved in NAADP action is the RyR (Figure 2);
techniques involved in these experiments were singlechannel recordings using reconstituted RyR in lipid planar
bilayers [36], specific inhibitors of RyR [35,37,38], and
knock down of RyR [37,38]. RyR as target of NAADP
may also involve an additional NAADP-binding protein
(Figure 2).
Similar to cADPR, administration of NAADP into intact
cells activates Ca2+ entry [38,39]. This may proceed via the
capacitative Ca2+ entry system (Figure 2), as discussed above
for cADPR or via activation of TRPM2 by NAADP [40].
However, very high concentrations of NAADP (EC50 =
730 µM) were necessary to activate TRPM2 [40].
Importantly, it has recently been shown that NAADP can
be taken up by cells, probably in a similar way as discussed
above for cADPR, opening the possibility for paracrine
functions of NAADP [41].
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The ADPR/TRPM2/Ca2+ signalling pathway
TRPM2 is a plasma membrane channel conducting Ca2+ (and
Na+ ) inflow. Although the presence of ADPR in cells was
already reported for erythrocytes in the early 1990s [42], it
took another 10 years until activation of TRPM2 was proposed by Perraud et al. [8] and Sano et al. [9].
The rationale to investigate the influence of ADPR on
TRPM2 function arose from the observation that the cytosolic C-terminal region of the channel protein contains a
domain that is homologous with the mitochondrial ADPRmetabolizing enzyme NUDT9 (Figure 3; [8]). Structural and
mutational analysis revealed direct binding of ADPR into
a cleft formed by the NUDT9 homology region, thereby
inducing the channel opening of TRPM2. Since the enzymatic
ADPR hydrolase activity is largely reduced in the NUDT9
homology region of the channel [8], this motif primarily
serves as an interaction site for ADPR.
Free ADPR is generated by different cellular pathways
(Figure 3): (i) the hydrolysis of NAD+ directly yields ADPR
and nicotinamide. This reaction is catalysed by NAD+ glycohydrolases (NADases), including the cell surface ectoenzymes CD38 and CD157 (reviewed in [7]) as well as a proposed mitochondrial NADase [43]; (ii) the subsequent action
of both PARPs [poly(ADPR) polymerases; PARP enzymes]
and poly(ADPR) glycohydrolases (PARG enzymes) indirectly generates ADPR via the formation and hydrolysis of
Cell and Molecular Biology of TRP Channels
poly(ADPR) residues on different proteins [44]; and
(iii) hydrolysis of cADPR (reviewed in [7]).
A signalling function of ADPR has become an attractive
hypothesis [45], although no direct experimental evidence
was available for this model until recently. Pharmacological
evidence points towards an elevation of cytosolic ADPR
levels upon challenging cells by oxidative stress [46]. Although most investigators demonstrated an indirect action of
H2 O2 by stimulating ADPR formation, also a direct action
of H2 O2 on TRPM2 was proposed (Figure 3). The first
direct demonstration of an increase in the cytosolic ADPR
concentration induced by extracellular stimulation was recently obtained in human T-cells [47], suggesting a second
messenger function of ADPR.
The regulation of TRPM2 gating by different ligands is
quite complex: e.g. the EC50 for activation of TRPM2 by
ADPR in patch–clamp experiments largely depends on the
concentration of free Ca2+ present in the pipette solution:
130 µM under complete chelation of Ca2+ [8] versus 12 µM
without Ca2+ buffering [48]. Binding of Ca2+ /calmodulin
sensitizes TRPM2 for the activation by ADPR via a positive
feedback mechanism. However, Ca2+ is just one ligand modulating the sensitivity of TRPM2 for ADPR: high concentrations of cADPR directly activate TRPM2 in the absence
of ADPR [48]. Lower concentrations, which are more in
the physiological range, positively modulate TRPM2 gating
by ADPR [48]. Recently, dependence of TRPM2 gating on
elevated temperatures was shown by Togashi et al. [49]:
temperatures above 35◦ C directly activated TRPM2 and positively modulated TRPM2 gating by ADPR, cADPR and
NAD+ . In contrast, the ADPR breakdown product AMP
possibly competes with ADPR for binding to the NUDT9
homology region, thereby negatively modulating TRPM2
function [48]. Recently, Beck et al. [40] reported the activation of TRPM2 by NAADP. However, the NAADP concentrations used in that study (EC50 = 730 µM) were several
orders of magnitude above the physiological NAADP concentrations reported in different cell systems, which are in
the low-nanomolar range [30,32,33]. Although an increase
in cellular NAADP levels upon stimulation was revealed
recently [30,32], a direct activation of TRPM2 by NAADP
seems unlikely. However, since these experiments were
performed in the whole cell patch–clamp mode, it cannot be
excluded that cytosolic components necessary for the interaction between NAADP and TRPM2 have been lost during
the experiment, resulting in the need for much higher
NAADP concentrations, as compared with the physiological
situation.
The physiological function of TRPM2 has just begun to
emerge. Early results demonstrating the activation of TRPM2
resulting in a massive Ca2+ overload induced by oxidative
stress, e.g. H2 O2 , supported a model connecting oxidative stress, Ca2+ influx via TRPM2 and apoptosis [45]. In the
last few years, these results were confirmed in a more physiological context, e.g. upon stimulation of insulinoma cells
by TNF-α (tumour necrosis factor α), granulocytes,
microglia cells or cardiomyocytes by H2 O2 , primary striatal
cells by amyloid β-peptide, or T-cells by concanavalin A.
Taken together, adenine-based, Ca2+ -regulating second
messengers are rapidly stepping into the focus of cellular signalling research. These novel messengers significantly enlarge
the Ca2+ signalling toolkit previously known. Their close
metabolic relationships indicate that conversion between
these nucleotides may be used as a powerful tool for the
fine-tuning of cell function.
We are grateful to our past and present co-workers and collaboration
partners. Research in our laboratory is supported by grants from the
Deutsche Forschungsgemeinschaft (no. GU 360/7-3/7-5/9-1/92/10-1), the Hertie-Foundation (no. 1.01.1/04/010, jointly with
Alexander Flügel, Max-Planck Institute of Neurobiology, Martinsried,
Germany), the Wellcome Trust (research collaboration grant
no. 068065, jointly with Barry Potter, University of Bath, Bath, U.K.)
and the Deutsche Akademische Austauschdienst (no. 423/vrc-PPPsr, jointly with Li-he Zhang, Peking University School of Pharmaceutical Sciences, Beijing, People’s Republic of China).
References
1 Sutherland, E.W. and Rall, T.W. (1957) J. Am. Chem. Soc. 79, 3608
2 Streb, H., Irvine, R.F., Berridge, M.J. and Schulz, I. (1983) Nature 306,
67–69
3 Berridge, M.J., Lipp, P. and Bootman, M.D. (2000) Nat. Rev. Mol. Cell Biol.
1, 11–21
4 Clapper, D.L., Walseth, T.F., Dargie, P.J. and Lee, H.C. (1987) J. Biol. Chem.
262, 9561–9568
5 Lee, H.C., Walseth, T.F., Bratt, G.T., Hayes, R.N. and Clapper, D.L. (1989)
J. Biol. Chem. 264, 1608–1615
6 Lee, H.C. and Aarhus, R. (1995) J. Biol. Chem. 270, 2152–2157
7 Schuber, F. and Lund, F.E (2004) Curr. Mol. Med. 4, 249–261
8 Perraud, A.L., Fleig, A., Dunn, C.A., Bagley, L.A., Launay, P., Schmitz, C.,
Stokes, A.J., Zhu, Q., Bessmann, M.J., Penner, R. et al. (2001) Nature 411,
595–599
9 Sano, Y., Inamura, K., Miyke, A., Mochizuki, S., Yokoi, H.,
Matsushime, H. and Furuichi, K. (2001) Science 293, 1327–1330
10 Guse, A.H. (2004) Curr. Mol. Med. 4, 239–248
11 Lee, H.C. (2004) Curr. Mol. Med. 4, 227–237
12 De Flora, A., Zocchi, E., Guida, L., Franco, L. and Bruzzone, S. (2004)
Ann. N.Y. Acad. Sci. 1028, 176–191
13 Guse, A.H. (2005) FEBS J. 272, 4590–4597
14 Liu, Q., Kriksunov, I.A., Graeff, R., Munshi, C., Lee, H.C and Hao, Q. (2005)
Structure 13, 1331–1339
15 Ceni, C., Muller-Steffner, H., Lund, F., Pochon, N., Schweitzer, A.,
De Waard, M., Schuber, F., Villaz, M. and Moutin, M.J. (2003)
J. Biol. Chem. 278, 40670–40678
16 Basile, G., Taglialatela-Scafati, O., Damonte, G., Armirotti, A.,
Bruzzone, S., Guida, L., Franco, L., Usai, C., Fattorusso, E., De Flora, A.
and Zocchi, E. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 14509–14514
17 Walseth, T.F., Aarhus, R., Kerr, J.A. and Lee, H.C. (1993) J. Biol. Chem.
268, 26686–26691
18 Noguchi, N., Takasawa, S., Nata, K., Tohgo, A., Kato, I., Ikehata, F.,
Yonekura, H. and Okamoto, H. (1997) J. Biol. Chem. 272, 3133–3136
19 Wagner, G.K., Guse, A.H. and Potter, B.V.L. (2005) J. Org. Chem. 70,
4810–4819
20 Moreau, C., Wagner, G.K., Weber, K., Guse, A.H. and Potter, B.V.L. (2006)
J. Med. Chem. 49, 5162–5176
21 Gu, X., Yang, Z., Zhang, L., Kunerth, S., Fliegert, R., Weber, K., Guse, A.H.
and Zhang, L. (2004) J. Med. Chem. 47, 5674–5682
22 Guse, A.H., Gu, X., Zhang, L., Weber, K., Kramer, E., Yang, Z., Jin, H., Li, Q.,
Carrier, L. and Zhang, L. (2005) J. Biol. Chem. 280, 15952–15959
23 Xu, J., Yang, Z., Dammermann, W., Zhang, L., Guse, A.H. and Zhang, L.-h.
(2006) J. Med. Chem. 49, 5501–5512
C 2007
Biochemical Society
113
114
Biochemical Society Transactions (2007) Volume 35, part 1
24 Guse, A.H., Berg, I., da Silva, C.P., Potter, B.V.L. and Mayr, G.W. (1997)
J. Biol. Chem. 272, 8546–85450
25 Guse, A.H., da Silva, C.P., Berg, I., Skapenko, A.L., Heyer, P.,
Hohenegger, M., Ashamu, G.A., Schulze-Koops, H., Potter, B.V.L. and
Mayr, G.W. (1999) Nature 398, 70–73
26 Partida-Sanchez, S., Cockayne, D.A., Monard, S., Jacobson, E.L.,
Oppenheimer, N., Garvy, B., Kusser, K., Goodrich, S., Howard, M.,
Harmsen, A. et al. (2001) Nat. Med. 7, 1209–1216
27 Kiselyov, K., Shin, D.M., Shcheynikov, N., Kurosaki, T. and Muallem, S.
(2001) Biochem. J. 360, 17–22
28 Feske, S., Gwack, Y., Prakriya, M., Srikanth, S., Puppel, S.H., Tanasa, B.,
Hogan, P.G., Lewis, R.S., Daly, M. and Rao, A. (2006) Nature 441,
163–165
29 Vig, M., Peinelt, C., Beck, A., Koomoa, D.L., Rabah, D.,
Koblan-Huberson, M., Kraft, S., Turner, H., Fleig, A., Penner, R.
and Kinet, J.P. (2006) Science 312, 1220–1223
30 Yamasaki, M., Thomas, J.M., Churchill, G.C., Garnham, C., Lewis, A.M.,
Cancela, J., Patel, S. and Galione, A. (2005) Curr. Biol. 15, 874–878
31 Graeff, R. and Lee, H.C. (2002) Biochem J. 367, 163–168
32 Gasser, A., Bruhn, S. and Guse, A.H. (2006) J. Biol. Chem. 281,
16906–16913
33 Churamani, D., Carrey, E.A., Dickinson, G.D. and Patel, S. (2004)
Biochem. J. 380, 449–454
34 Churchill, G.C., Okada, Y., Thomas, J.M., Genazzani, A.A., Patel, S. and
Galione, A. (2002) Cell 111, 703–708
35 Gerasimenko, J.V., Maruyama, Y., Yano, K., Dolman, N.J., Tepikin, A.V.,
Petersen, O.H. and Gerasimenko, O.V. (2003) J. Cell Biol. 163, 271–282
36 Hohenegger, M., Suko, J., Gscheidlinger, R., Drobny, H. and Zidar, A.
(2002) Biochem. J. 367, 423–431
C 2007
Biochemical Society
37 Langhorst, M.F., Schwarzmann, N. and Guse, A.H. (2004) Cell. Signalling
16, 1283–1289
38 Dammermann, W. and Guse, A.H. (2005) J. Biol. Chem. 280,
21394–21399
39 Moccia, F., Lim, D., Nusco, G.A., Ercolano, E. and Santella, L. (2003)
FASEB J. 17, 1907–1909
40 Beck, A., Kolisek, M., Bagley, L.A., Fleig, A. and Penner, R. (2006)
FASEB J. 20, 962–964
41 Billington, R.A., Bellomo, E.A., Floriddia, E.M., Erriquez, J., Distasi, C. and
Genazzani, A.A. (2006) FASEB J. 20, 521–523
42 Guida, L., Zocchi, E., Franco, L., Benatti, U. and De Flora, A. (1992)
Biochem. Biophys. Res. Commun. 188, 402–408
43 Zhang, J., Ziegler, M., Schneider, R., Klocker, H., Auer, B. and
Schweiger, M. (1995) FEBS Lett. 377, 530–534
44 Gagne, J., Hendzel, M.J., Droit, A. and Poirier, G.G. (2006) Curr. Opin.
Cell Biol. 18, 145–151
45 Ayub, K. and Hallett, M.B. (2004) FASEB J. 18, 1335–1338
46 Hara, Y., Wakamori, M., Ishii, M., Maeno, E., Nishida, M., Yoshida, T.,
Yamada, H., Shimizu, S., Mori, E., Kudoh, J. et al. (2002) Mol. Cell 9,
163–173
47 Gasser, A., Glassmeier, G., Fliegert, R., Langhorst, M.F., Meinke, S.,
Hein, D., Kruger, S., Weber, K., Heiner, I., Oppenheimer, N. et al. (2006)
J. Biol. Chem. 281, 2489–2496
48 Kolisek, M., Beck, A., Fleig, A. and Penner, R. (2005) Mol. Cell 18, 61–69
49 Togashi, K., Hara, Y., Tominaga, T., Higashi, T., Konishi, Y., Mori, Y. and
Tominaga, M. (2006) EMBO J. 25, 1804–1815
Received 18 August 2006