Abbreviations ADPRC, ADP-ribosyl cyclase; 8-Br-N1-cIDPR, 8-bromo-cyclic inosine diphosphoribose; cADPcR, cyclic ADP carbocyclic ribose; cADPR, cyclic adenosine diphosphoribose; cADPR-BP,
Trang 1Second messenger function and the structure–activity
relationship of cyclic adenosine diphosphoribose (cADPR) Andreas H Guse
University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, Cellular Signal Transduction, Hamburg, Germany
The cyclic ADP-ribose ⁄ Ca2+signalling
pathway
Cyclic ADP-ribose (cADPR) was discovered in 1987 as
a Ca2+ mobilizing metabolite of the well-known
co-enzyme b-nicotinamide adenine dinucleotide (NAD) by
Lee and coworkers [1] The cyclic structure of cADPR
was initially predicted to originate from an N-glycosyl
linkage between the anomeric carbon of the ribose,
which in the precursor NAD is linked to nicotinamide,
and the amino⁄ imino group at C6 of the adenine
moiety [2] Spectroscopic data [3] and finally a crystal
structure revealed cyclization between the anomeric
C1 of this ribose moiety (commonly termed ‘northern
ribose’ while the ribose linked to N9 of adenine is called the ‘southern’ ribose; Fig 1) and the N1 of the adenine ring [4]
Besides d-myo-inositol 1,4,5-trisphosphate (InsP3) and nicotinic acid adenine dinucleotide phosphate (NAADP; reviewed in [4a]), cADPR is one of the prin-cipal Ca2+-releasing second messengers involved in cel-lular Ca2+ homeostasis Changes in the cellular Ca2+ homeostasis are among the fundamental signalling pro-cesses in multicellular organisms Such changes occur
in response to extracellular signals, e.g hormones, mediators, cell–cell contacts or physical stimuli, and represent one of the most important, powerful and ver-satile intracellular signal transducers Changes in the
Correspondence
A H Guse, University Medical Center
Hamburg-Eppendorf, Center of Experimental
Medicine, Institute of Biochemistry and
Molecular Biology I: Cellular Signal
Transduction, Martinistr 52,
20246 Hamburg, Germany
Fax: +49 40 42803 9880
Tel: +49 40 42803 2828
E-mail: guse@uke.uni-hamburg.de
(Received 10 March 2005, accepted 05 July
2005)
doi:10.1111/j.1742-4658.2005.04863.x
Cyclic ADP-ribose (cADPR) is a Ca2+mobilizing second messenger found
in various cell types, tissues and organisms Receptor-mediated formation
of cADPR may proceed via transmembrane shuttling of the substrate NAD and involvement of the ectoenzyme CD38, or via so far unidentified ADP-ribosyl cyclases located within the cytosol or in internal membranes cADPR activates intracellular Ca2+ release via type 2 and 3 ryanodine receptors The exact molecular mechanism, however, remains to be elucida-ted Possibilities are the direct binding of cADPR to the ryanodine receptor
or binding via a separate cADPR binding protein In addition to Ca2+ release, cADPR also evokes Ca2+entry The underlying mechanism(s) may comprise activation of capacitative Ca2+ entry and⁄ or activation of the cation channel TRPM2 in conjunction with adenosine diphosphoribose The development of novel cADPR analogues revealed new insights into the structure–activity relationship Substitution of either the northern ribose or both the northern and southern ribose resulted in much simpler molecules, which still retained significant biological activity
Abbreviations
ADPRC, ADP-ribosyl cyclase; 8-Br-N1-cIDPR, 8-bromo-cyclic inosine diphosphoribose; cADPcR, cyclic ADP carbocyclic ribose; cADPR, cyclic adenosine diphosphoribose; cADPR-BP, cADPR binding protein; cArisDPR, cyclic aristeromycin diphosphoribose; N1-cIDPR, N1-coupled cyclic inosine diphosphoribose; cIDP-DE, N1-[(phosphoryl-O-ethoxy)-methyl]-N9-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthine-cyclic pyro-phosphate; cIDPRE, N1-ethoxymethyl-cIDPR; CRAC, Ca 2+ release activated Ca 2+ channel; FKBP, FK506 binding protein; InsP3, D -myo-inositol 1,4,5-trisphosphate; NAADP, nicotinic acid adenine dinucleotide phosphate; RyR, ryanodine receptor; TRP, transient receptor potential.
Trang 2cellular Ca2+ homeostasis finally result in meaningful
physiological response of the cell Thus, intracellular
Ca2+signalling is one of the most important
transduc-tion systems to integrate physiological responses of
multicellular organisms
Because the free cytosolic and nuclear Ca2+
concen-tration ([Ca2+]i) is kept fairly low (approximately
50–100 nm) by ATP-driven Ca2+ pumps located in
both the plasma membrane and intracellular
mem-branes (reviewed in [5]), rapid increases of [Ca2+]ican
be achieved by increasing the open probability of
Ca2+ channels, either localized in the membranes of intracellular Ca2+ stores or in the plasma membrane Such Ca2+ entry channels in the plasma membrane and Ca2+ release channels in intracellular membranes have been reviewed in the past [6–11] Review articles dealing with the cADPR⁄ Ca2+ signalling system, the topic of this article, have also been published in the last two years [12–16] Thus, I will not repeat in detail the topics presented in those reviews, but I will briefly describe the hallmarks of the cADPR⁄ Ca2+ signalling system Subsequently I will spend more time in discuss-ing recent finddiscuss-ings related to the biological activity of cADPR analogues and some clues regarding the struc-ture–activity relationship of cADPR
The cADPR⁄ Ca2+ signalling system is active in diverse cellular systems, including smooth, skeletal and cardiac muscle, neuronal and neuronal-related cells, hemopoietic cells, acinar cells, and oocytes (for a more complete list see [15]) Because the cADPR⁄ Ca2+ sig-nalling system was also observed in protozoa and plant cells, it appears to be a phylogenetically old and con-served system As for the InsP3⁄ Ca2+ signalling sys-tem, in several cell types extracellular stimuli activate cADPR-forming enzymes called ADP-ribosyl cyclases
Fig 2 Receptor-mediated formation, metabolism and sites of action of cADPR Dotted lines indicate minor pathway or relations not gener-ally accepted or proven Cx43, connexin 43; CRAC, Ca2+release-activated Ca2+channel; cADPRH, cADPR-hydrolase.
Fig 1 Structure of cADPR.
Trang 3(ADPRC) and thereby induce the formation of
cADPR (Fig 2) G-protein coupling and Tyr
phos-phorylation have been implicated in ADPRC
activa-tion [17,18]
The enzymes responsible for the synthesis of cADPR
are still a matter of debate An ADPRC that acts
mainly as a cyclizing enzyme has been purified and
cloned more than 10 years ago from the ovotestis of
Aplysia californica [19,20] Mammalian homologues of
this enzyme are the membrane proteins CD38 and
CD157 (reviewed in [21]) After their discovery it was
surprising to note that their catalytic sites are located
outside of the cell (or in intracellular vesicles), but
obviously not in direct contact to the substrate NAD
and the intracellular Ca2+ release channel sensitive to
cADPR, the ryanodine receptor (RyR) This situation
has been described as the ‘topological paradox’ of the
cADPR⁄ Ca2+ signalling system [22] De Flora and
coworkers have worked out a potential solution for
this problem They found that NAD can leave the cell
via connexin 43 hemichannels (Fig 2; [23]) Outside
the cell (or inside CD38 containing vesicles) NAD is
then converted, at least in part, to cADPR Evidence
was presented that both CD38 and nucleoside
trans-porters act as cADPR-transporting proteins (Fig 2;
[24]) This system in principle represents a solution for
the topological paradox However, connexin 43
hemi-channels appear to be open for NAD export only at
[Ca2+]i 100 nm, indicating that this system is
un-likely to operate when [Ca2+]i is elevated above
nor-mal basal levels [25] On the other hand, ectoenzymes
producing cADPR (such as CD38 and CD157) and
transport systems for cADPR in the plasma membrane
open the possibility that cADPR acts as a paracrine
signalling molecule (reviewed in [14]) Indeed, recently
a potentially very important example for such a
para-crine intercellular signalling molecule was described
CD157-(BST-1)-positive bone marrow stromal cells via
production of extracellular cADPR induced the
expan-sion of human hemopoietic progenitor cells [26] A
crucial point in this intercellular signalling pathway
appears to be the expression of concentrative
nucleo-side transporters in the hemopoietic progenitors since
this allows uptake of a sufficient amount of cADPR
into the target cells [26]
In addition to the relatively complicated system for
cADPR synthesis described above, several reports
sug-gest expression of either cytosolic or membrane-bound
enzymes not related to CD38 or CD157 [18,27–31]
None of these enzymes have been identified on the
molecular level so far; however, some (or all) of them
might be located at cellular sites more suitable for
rapid formation of intracellular cADPR
Ca2+release by cADPR via ryanodine receptors
Whatever these enzymes turn out to be, receptor-medi-ated formation of cADPR obviously takes place in many cell types and cADPR acts on the type 2 and⁄ or type 3 RyR This interaction was initially demonstra-ted by the sensitivity of cADPR-mediademonstra-ted Ca2+release
to pharmacological inhibitors of RyR, such as ruthen-ium red or inhibitory concentrations of ryanodine [32] and has since been confirmed in many cell systems Moreover, molecular knock-down of type 3 RyR in T-lymphocytes resulted in a significant reduction of cADPR-induced Ca2+ release, also suggesting such an interaction [33]
However, the exact molecular mechanisms under-lying this interaction are poorly studied In the first study to identify a cADPR receptor, [32P]8-N3-cADPR was used to covalently label putative cADPR binding proteins (cADPR-BP) in sea urchin eggs [34] As pro-teins of 100 and 140 kDa were labelled, it was conclu-ded that either proteolytic fragments of RyR were labelled or that a distinct cADPR-BP mediated the effects at the RyR (Fig 2) A putative direct binding site of cADPR at the RyR has not been described so far In contrast, in a limited number of cell systems FK506 binding protein 12.6 (FKBP 12.6, calstabin2) was found to bind cADPR and to mediate responsive-ness of RyR towards cADPR [35,36] The data sup-port a model in which binding of FKBP 12.6 to RyR decreases its open probability, whereas binding of cADPR or FK506 to FKBP 12.6 weakens the inter-action between FKBP 12.6 and RyR, thereby resulting
in an increased open probability of RyR
Other studies have shown that in specific cell sys-tems additional proteins must be present, e.g that cal-modulin effectively decreases the EC50 for cADPR in sea urchin egg homogenates [37] or that Tyr phos-phorylation of the RyR enhances its responsiveness to cADPR [38]
In addition to Ca2+release via RyR, cADPR has been demonstrated to activate Ca2+ entry [18,39,40] Ini-tially, it was shown that microinjection of cADPR into Jurkat T-cells induced long-lasting trains of Ca2+ spikes that were blocked by addition of Zn2+ or SKF96365 [39] Preincubation with the specific cADPR antagonist 7-deaza-8-Br-cADPR abolished long-lasting
Ca2+signalling evoked by T-cell receptor⁄ CD3 ligation [18] Evidence for cADPR involvement in calcium entry was also obtained in neutrophils [40] The chemotatic
Trang 4peptide fMLP induced biphasic calcium signalling –
calcium release followed by calcium entry – in
neu-trophils from wild type mice The calcium entry phase
was blocked by 8-Br-cADPR, a cADPR antagonist
Furthermore, fMLP did not elicit the calcium entry
response in neutrophils from Cd38–⁄ – mice The
Cd38–⁄ –neutrophils lack the ability to produce cADPR
[40] These data suggest that cADPR, in addition to
Ca2+release, also promotes Ca2+entry
What are the underlying mechanisms? A
mechan-ism generally assumed to play a role in nonexcitable
cells is the capacitative Ca2+ entry mechanism
[reviewed in 7,41,42] Ca2+ currents with very low
amplitude activated by store-depletion have been
detected in several nonexcitable cells types [43,44]
Evidence for activation of store-operated Ca2+ entry
secondary to cADPR-mediated Ca2+ release (Fig 2)
was obtained in RyR knock-down Jurkat T-cells in
which the long-lasting phase of Ca2+ signalling was
partially reduced in amplitude [33] Moreover,
appli-cation of cADPR into InsP3 receptor-deficient DT40
cells evoked CRAC-like plasma membrane currents
[45] Extracellular addition of the novel
membrane-permeant cADPR agonists N1-ethoxymethyl-cIDPR
(cIDPRE) and
N1-[(phosphoryl-O-ethoxy)-methyl]-N9-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthine-cyclic
pyrophosphate (cIDP-DE) to intact T-cells employing
a Ca2+-free⁄ Ca2+-reintroduction protocol also
sug-gests capacitative Ca2+ entry secondary to Ca2+
release evoked by cADPR [46,47] In recent years, the
plasma membrane ion channel transient receptor
potential – melastatin-like (TRPM2) has gained
atten-tion because it is activated by adenosine
diphospho-ribose (ADPR), which is synthesized from NAD by
CD38-type ADPRC and which is also a breakdown
product of cADPR (Fig 2) TRPM2 is a Ca2+- and
Na+-permeable cation channel that is mainly
expressed in the brain and in cells of the immune
sys-tem [48–50] The nudix box in the cytosolic
C-ter-minal region of TRPM2, a conserved motif of
enzymes with nucleotide pyrophosphatase activity,
appears to bind ADPR and regulate TRPM2
[48,49,51] Very recently, it was shown that cADPR
can also activate TRPM2 [52] Activation of TRPM2
by cADPR alone resulted in very small currents and
was observed only at very high cADPR
concentra-tions (EC50¼ 700 lm; [52]); such concentrations
likely are not present in cells, as determination of
cADPR usually resulted in low micromolar
concen-trations (e.g [18]) Most interestingly, a likely
physio-logical concentration of 10 lm cADPR shifted the
EC50 for ADPR from 12 lm to 90 nm [52] Thus,
cADPR appears to be a potent coregulator for Ca2+
(and Na+) entry via TRPM2 The situation, however, appears to be more complex because physiological concentrations of AMP inhibit the effect of ADPR
on TRPM2 channel gating The individual contribu-tion of each of these nucleotides to the regulacontribu-tion of
Ca2+ entry under physiological conditions, e.g with-out washwith-out of endogenous intracellular compounds, will require further investigation in the future
Structure–activity relationship of cADPR
In-depth reviews covering the chemistry and biological activity of many cADPR analogues have been pub-lished [16,53–55] and the reader interested in more complete coverage of the subject may refer to these review articles However, I will focus on an interesting series of agonistic cADPR analogues recently devel-oped When analysing the Ca2+-mobilizing properties
of derivatives modified in the northern ribose of cADPR in permeabilized T-cells, it was observed that replacement of the hydroxyl group at C2¢¢ [for clarity atoms of the ‘northern ribose’ will be marked as dou-ble prime (¢¢) while atoms in the southern ribose will
be marked as single prime (¢)] by an amino group was almost without effect on the EC50 of Ca2+ release (Fig 3; [56]) This indicates that at this side of the molecule either the polar interactions with its interact-ing protein were fully replaced by the amino group or that no or only minor ligand protein interactions took place Astonishingly, another modification of the nor-thern ribose, cyclic ADP carbocyclic ribose (cADPcR; Fig 3), showed weaker Ca2+release activity indicating that the oxygen atom of the northern ribose is indeed important for Ca2+ release [56] This situation is unique for the northern ribose since replacement of the oxygen by a carbocyclic bridge in the southern ribose
in the molecule termed cyclic aristeromycin diphos-phoribose (cArisDPR, Fig 3; [57]) did not significantly alter its Ca2+ releasing potential in permeabilized T-cells [56] These data indicate that both ribose moie-ties might be suitable targets for additional and more radical modifications
Besides modifications in the ribose moieties, novel analogues modified in the nucleobase show that the base hypoxanthine can replace adenine without loss
of biological activity [58] This is true for
N1-cID-PR, a cyclic molecule in which the cyclic bond is made between the anomeric C1 of the northern ribose and N1 of inosine (Fig 4), while N7-cIDPR showed no Ca2+ release activity in sea urchin egg homogenates [59] Indeed, Ca2+ release activity of inosine derivatives was first described for a series of
Trang 5cIDPR analogues that were cyclized between N1 of
inosine and C2 of the northern ribose [60] In
addi-tion, 8-Br-N1-cIDPR induced Ca2+ signalling in
intact T-cells [61,62] This finding was surprising since 8-Br-N1-cADPR is a well-known antagonist of cADPR [63]
Fig 3 Ca 2+ -releasing activity of some southern and northern ribose modified cADPR analogues.
Fig 4 Ca2+-releasing activity of some cIDPR analogues.
Trang 6A combination of nucleobase and ribose
modifica-tions led to the development of an
N1-ethoxymethyl-cIDPR (N1-ethoxymethyl-cIDPRE) in which the northern ribose was
replaced by an ether strand mimicking the
C1-O-C4⁄ C5 part of the original ribose (Fig 4; [46]) Despite
this enormous modification the compound was a
par-tial agonist in permeabilized T-cells and induced both
local and global Ca2+ signalling in intact T-cells [46]
8-Azido- and 8-NH2-cIDPRE performed similarly
(Fig 4) whereas the halogenated compounds 8-Br- and
8-Cl-cIDPRE were almost without effect (Fig 4; [46])
An even stronger modification of the original molecule
cADPR was achieved by substitution of both the
nor-thern and sounor-thern ribose by ether strands, resulting
in
N1-[(phosphoryl-O-ethoxy)-methyl]-N9-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthine-cyclic pyrophosphate
(cIDP-DE; Fig 4) This compound was a partial
agon-ist in permeabilized cells and, when applied
extracellu-larly to intact T-cells, induced biphasic Ca2+signalling
comparable to T-cell receptor⁄ CD3 stimulation [47]
The biological activity of cIDP-DE is not restricted to
T-lymphocytes; extracellular addition to intact mouse
cardiac myocytes revealed activation of subcellular
Ca2+ signalling and the induction of global Ca2+
waves, which occurred in an oscillatory manner [47]
In terms of structure–activity relationship these data
indicate that the northern and southern riboses are
pri-marily necessary as linkers between the base adenine
(or hypoxanthine) and the diphospho-bridge, as they
can be replaced by much simpler ether strands These
ether strands mimic the distance between the
nucleo-base and the diphospho-bridge, but on the other hand
likely are involved in polar interactions with the
cADPR receptor protein Certainly, the natural
lin-kers, the northern and southern ribose moieties, do a
better job, as can be seen from the quantitative
com-parison with cADPR [47], probably by allowing more
interactions, but the new analogues open the
possibil-ity for the development of further, perhaps even more
simple compounds with biological activity Such
com-pounds might be more suitable for pharmaceutical
applications as compared to the cADPR analogues
available so far
Conclusion
Although the molecular mechanism of
receptor-medi-ated formation of cADPR is still mysterious in many
aspects, significant advancements were achieved by
demonstrating that the topological paradox of
extracel-lular⁄ intravesicular CD38 can be circumvented by
spe-cific transport processes of the substrate NAD and the
second messenger cADPR In addition, the description
of novel, non-CD38-like ADPRC may be a good start-ing point for their identification in the near future The use of novel inosine-based cyclic nucleotides signifi-cantly added to our understanding of the structure– activity relationship of cADPR Finally, a potential new mechanism underlying Ca2+ entry mediated by cADPR may, in addition to capacitative Ca2+ entry, involve gating of TRPM2 in conjunction with ADPR
Acknowledgements
I am grateful to my coworkers and collaboration part-ners for their continuous support Thanks are also expressed to Tim Walseth (Minneapolis, USA) for crit-ically reading the manuscript Research in my lab is supported by grants from the Deutsche Forschungs-gemeinschaft (no GU 360⁄ 7-3 ⁄ 9-1 ⁄ 9-2/10-1), the Hertie-Foundation (no 1.01.1⁄ 04 ⁄ 010, jointly with Alexander Flu¨gel, Martinsried, Germany), the Well-come Trust (research collaboration grant no 068065 jointly with Barry Potter, Bath, UK) and the Deutsche Akademische Austauschdienst (no 423⁄ vrc-PPP-sr, jointly with Li-he Zhang, Beijing, China)
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