| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen’s Medical Center, and John A. Burns School of Medicine at the University of Hawaii, Honolulu, Hawaii, USA
2Correspondence: Center for Biomedical Research, The Queen’s Medical Center, 1301 Punchbowl St. UHT 8, Honolulu, HI 96813. E-mail: rpenner{at}hawaii.edu.
ABSTRACT
TRPM2 (previously designated TRPC7 or LTRPC2) is a Ca2+-permeable nonselective cation channel that contains a C-terminal enzymatic domain with pyrophosphatase activity, which specifically binds ADP-ribose. Cyclic ADP-ribose (cADPR) and hydrogen peroxide (H2O2) can facilitate ADPR-mediated activation of heterologously expressed TRPM2. Here, we show that the two Ca2+-mobilizing second messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) strongly activate natively expressed TRPM2 channels in Jurkat T cells. TRPM2 activation by both agonists can be partially suppressed by the ADPR antagonist adenosine monophosphate (AMP), which suggests that cADPR and NAADP lead to mobilization of endogenous ADPR presumably via metabolic conversion. The remaining channel activity is due to direct gating of TRPM2 by the two agonists and can be completely suppressed by 8-Br-cADPR, which suggests that cADPR and NAADP share a common binding site on TRPM2 that can regulate TRPM2 activity in synergy with ADPR. We conclude that cADPR and NAADP, in combination with ADPR, represent physiological co-activators of TRPM2 that contribute to Ca2+ influx in T lymphocytes and presumably other cell types that express this channel.— Beck, A., Kolisek, M., Bagley, L. A., Fleig, A., Penner, R. Nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T lymphocytes.
Key Words: TRPM2 • cADPR • NAADP
THE TRPM2 ION channel, previously named TRPC7 (1)
or LTRPC2 (2
, 3)
and recently designated TRPM2 (4)
, has been shown to be a nonselective cation channel specifically gated by ADP-ribose (ADPR) (2
, 3)
. Intracellular Ca2+ cannot activate TRPM2 by itself but appears to be an important modulator and cofactor of TRPM2, as elevated [Ca2+]i can significantly increase the sensitivity of TRPM2 toward ADPR, enabling it to gate the channel at lower concentrations (2
, 5)
. Early reports suggested that TRPM2 can also be gated by H2O2 (6)
and high concentrations of NAD+ (3
, 6
, 7)
, however, recent evidence suggests that the NAD+ effect is likely due to contaminations of commercially available NAD+ with ADPR and H2O2 has only very limited efficacy in activating TRPM2 directly (8)
. H2O2’s primary mechanism of action appears to involve a facilitation of ADPR-mediated activation of TRPM2 (8)
, which is consistent with its apparent requirement for a functional ADPR binding site in the Nudix domain of the channel (9
, 10)
. In close analogy to H2O2, cyclic ADP-ribose (cADPR) has recently been introduced as a further agonist for TRPM2 activation. It also has a limited ability to activate the channel directly but greatly potentiates ADPR-induced gating by shifting ADPR’s half-maximal effective concentration from micromolar to nanomolar levels (8)
.
While TRPM2 is dominantly expressed in the brain, it is also detected in many other tissues, including bone marrow, spleen, heart, leukocytes, liver, and lung. Native TRPM2 currents have been recorded from the U937 monocyte cell line (2)
, neutrophils (7)
, microglia (11)
, and CRI-G1 insulinoma cells (12)
, where ADPR induces large cation currents (designated IADPR) that closely match those mediated by heterologously expressed TRPM2. Interestingly, many of the cell types in which TRPM2 is expressed (e.g., lymphocytes, neutrophils, pancreatic beta cells) have also been reported to utilize cADPR as a second messenger for Ca2+ signaling [for reviews see (13
14
15
16
17
18
19)
]. Cyclic ADP-ribose is synthesized from its precursor NAD+ by ADP-ribosyl cyclases (e.g., CD38) and has long been thought to function as an endogenous regulator of Ca2+-induced Ca2+ release via ryanodine receptors. However, recent evidence has indicated that cADPR may also be involved in Ca2+ influx (20
21
22)
, and the discovery of its ability to target TRPM2 suggests that this Ca2+-permeable channel may account for that effect (8)
. A further messenger that has emerged as Ca2+ release agonist is nicotinic acid adenine dinucleotide phosphate (NAADP) (18
, 23
24
25)
, which can also be produced by CD38 from NADP. However, its molecular target has not yet been identified. Some studies suggest that NAADP, like cADPR, targets the ryanodine receptor, whereas others suggest an unknown release channel. Some evidence also points to a role of NAADP in Ca2+ influx (26)
. Both cADPR and NAADP have recently been found to be differentially produced following receptor stimulation and appear to serve a key role in initiating and maintaining cellular signaling in pancreatic acinar cells (27)
. In the present study, we have analyzed the effects of cADPR and NAADP on human TRPM2 channels expressed both heterologously in HEK-293 cells and natively in Jurkat T lymphocytes. We find that both messengers can activate these channels either directly and/or in synergy with ADPR and can, therefore, be regarded as genuine second messengers in support of Ca2+ influx.
MATERIALS AND METHODS
Cell culture
Tetracycline-inducible HEK-293 Flag-TRPM2-expressing cells (9
, 10)
were cultured at 37°C with 5% CO2 in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% FBS, blasticidin (5 µg ml–1; Invitrogen, Carlsbad, CA) and zeocin (0.4 mg ml–1; Invitrogen). One to two days before the experiments, cells were resuspended in medium and plated on glass cover slips. TRPM2 expression was induced by 1 µg ml–1 tetracycline (Invitrogen) 15 h prior to experiments. Jurkat T cells were cultured at 37°C with 5% CO2 in RPMI 1640 medium supplemented with 10% FBS.
Solutions
For patch-clamp experiments, cells were kept in standard Ringer’s solution (in mM): 140 NaCl, 2.8 KCl, 1 CaCl2, 2 MgCl2, 10 glucose, 10 HEPES·NaOH (pH 7.2 adjusted with NaOH). Standard pipette-filling solutions contained (in mM): 140 Cs-glutamate, 8 NaCl, 1 MgCl2, 10 Cs-BAPTA, 10 HEPES·CsOH (pH 7.2 adjusted with CsOH). In some experiments Cs-glutamate was replaced by K-glutamate, and Cs-BAPTA by K-BAPTA. In some other experiments, calcium was left unbuffered by leaving out any calcium chelator. Jurkat T cells were plated on coverslips coated with 25% polylysine 4–8 h before performing single-channel experiments using the inside-out configuration. Here, [Ca2+]i and [Ca2+]e were buffered to 200 nM with 10 mM BAPTA and 4.9 mM CaCl2. All nucleotides and reagents were purchased from Sigma and dissolved in standard intracellular solution.
Electrophysiology
Patch-clamp experiments were performed in the whole-cell configuration at 21–25°C. All data were acquired with Pulse software controlling an EPC-9 amplifier (HEKA, Lambrecht, Germany) and analyzed using PulseFit (HEKA) and Igor Pro (Wavemetrics). Voltage ramps of 50 ms spanning the voltage range from –100 to + 100 mV were delivered from a holding potential of 0 mV at a rate of 0.5 Hz over a period of 200–500 s. When applicable, voltages were corrected for liquid junction potentials. Currents were filtered at 2.9 kHz and digitized at 100 µs intervals. Capacitive currents and series resistance were determined and corrected before each voltage ramp. For analysis, the very first current records before the activation of currents were digitally filtered at 2 kHz, pooled, and used for leak-subtraction of all subsequent records. The ramp current amplitudes at –80 mV (inward current) and +80 mV (outward current) were extracted from the leak-subtracted individual ramps and displayed as current development over time. Some individual ramps were displayed as representative current–voltage (I–V) relationships. Single-channel activity was recorded in the inside-out configuration and currents were filtered and sampled as above. Patches were pulled from Jurkat T cells and first exposed to the standard intracellular solution with [Ca2+]i clamped to 200 nM. After 1 min of recordings in this solution, patches were exposed to the same solution supplemented with either 300 µM ADPR or 300 µM cADPR and monitored for channel activity. Single-channel data acquisition was performed using fixed voltage steps of 11 s duration given in 20 mV increments between –80 mV and +80 mV from a holding potential of 0 mV. For display purposes, data records were digitally filtered and down-sampled to 100 Hz.
RESULTS
Northern blotting has indicated that TRPM2 is expressed in a variety of tissues and cell types, including immunocytes (1
2
3)
. Further, ADPR has been shown to produce IADPR in monocyte and T lymphocyte cell lines (2
, 3)
. To determine the characteristics of the IADPR in Jurkat T lymphocytes, we performed whole-cell experiments using both ADPR and cADPR as channel activators. These experiments were performed under relatively physiological conditions in which [Ca2+]i was left unbuffered and allowed to vary freely by leaving out any extrinsic calcium chelators. Our data revealed a maximum whole-cell inward current of 
500 pA at 1 mM internal ADPR (Fig. 1
A). A similar current size was reached at doses as low as 10 µM, with longer times to reach maximum current as concentrations decreased. Similarly, cADPR induced maximum inward current sizes of around 600 pA (Fig. 1B
), but required slightly higher concentrations than ADPR and was effective at concentrations of 100 µM or higher. The linear current-voltage relationships of the currents produced by either agonist were indistinguishable from each other (Fig. 1C
). The dose-response relationships derived from these whole-cell currents are shown in Fig. 1D
. The half-maximal effective concentration (EC50) for cADPR was found to be 60 µM and that of ADPR was 10 µM. These data indicate that the IADPR channel can be gated by both ADPR and cADPR in lymphocytes, although under these experimental conditions these cells are more sensitive to ADPR as a gating mechanism than to cADPR.
|
To establish whether ADPR and cADPR could directly affect the IADPR channel in Jurkat cells, we applied either of these agonists to the internal side of cell-free inside-out membrane patches. Individual channel openings were observed using both ADPR and cADPR (Fig. 1E
), though ADPR induced channel activity in only 11 out of 58 patches (19%), and cADPR was effective in 15 out of 111 patches (14%). However, patches that exhibited ADPR/cADPR-responsive channels often contained several ion channels, indicating that native channels in lymphocytes may be clustered. The current-voltage relationships derived from these inside-out patches are shown in Fig. 1F
and are virtually indistinguishable. The single-channel conductance, obtained by linear fits, were 67 pS for ADPR and 69 pS for cADPR. These data indicate that the IADPR channel in Jurkat cells can be gated directly by either ADPR or cADPR in cell-free excised membrane patches.
The above results confirm our previous observation that cADPR can indeed regulate TRPM2 activity (8)
. The main difference we observed between heterologously expressed TRPM2 and the native IADPR in T cells was that the sensitivity of IADPR toward cADPR appears to be significantly lower in T cells (EC50 = 60 µM) compared with HEK-293 cells (EC50 = 120 µM). In addition, the maximal current amplitudes obtained by cADPR in T cells are comparable to those achieved by ADPR, whereas our previous study found only a rather limited extent of cADPR-mediated activation, typically amounting to less than 5% of the maximal current induced by ADPR (8)
. We considered that one possible reason for this discrepancy might reside in different intracellular pipette solutions used by the two studies, since the above T cell experiments were all performed using Cs-glutamate-based pipette solutions to minimize the lymphocyte’s endogenous K+ currents, whereas our previous study on heterologously expressed TRPM2 in HEK-293 cells was performed with K-glutamate-based solutions.
To determine whether Cs+ might account for the enhanced cADPR responses in T cells, we reassessed the ADPR and cADPR effects in both T cells and HEK-293 cells using K- and Cs-glutamate-based pipette solutions. As illustrated in Figs. 2
A and B, both ADPR and cADPR dose-dependently activated IADPR currents in K+-based solutions. We found no significant change in the apparent sensitivity of TRPM2 to either ADPR (Fig. 2C
) or cADPR (Fig. 2D
); the half-maximal effective concentrations for ADPR in the presence of Cs+ and K+ were 7 and 15 µM, respectively, and for cADPR they were 60 µM in both cases. The ADPR values are in close agreement to the EC50 values we determined in HEK-293 cells in Cs+ and K+-based solutions 15 and 12 µM, respectively (Fig. 2E
). In both cell types, the maximal ADPR-induced current amplitudes were slightly smaller in the presence of Cs+, suggesting that Cs+ may actually reduce channel open probability. In contrast, we observed significant differences in the behavior of TRPM2 in both cell types when stimulating with cADPR. In T cells (Fig. 2D
), TRPM2’s sensitivity toward cADPR was unchanged, but current amplitudes were generally larger in the presence of Cs+. In HEK-293 cells (Fig. 2F
), as previously reported, cADPR was not very effective in K+-based solutions, but Cs+ shifted the EC50 by a factor of 6 from 700 µM in the presence of K+ to 120 µM in Cs+-based solutions. In addition, the maximal cADPR-induced current amplitudes were larger in the presence of Cs+, reaching levels normally only obtained with ADPR. Thus, the overall sensitivity of the native channels in lymphocytes toward cADPR remains significantly higher than that of heterologously expressed TRPM2 in HEK-293 cells under either ionic condition.
|
The above results indicate that Cs+ ions can enhance cADPR-mediated gating of TRPM2 compared with the more physiological cation K+. In HEK-293 cells, it causes a shift in the apparent EC50 to lower concentrations and in both HEK-293 cells and T cells it enhances maximal current amplitudes. It seems unlikely that this facilitatory effect is due to a direct action on the channel’s functional properties, since Cs+ does not significantly affect EC50 values of ADPR-mediated currents and current amplitudes are actually reduced rather than enhanced. It is also unlikely that Cs+ simply enhances cADPR’s affinity for TRPM2, since there is no shift in the apparent EC50 for cADPR in T cells. This finding suggests that the differences observed in T cells and HEK-293 cells are likely based on the cellular environment the channels are embedded in. For example, Cs+ might mobilize endogenous ADPR either by releasing it from internal compartments such as mitochondria or by enhancing the enzymatic production of ADPR from cADPR, which would then synergize with cADPR to produce enhanced TRPM2 activity. Since T cells express native nucleotide-regulated TRPM2 channels, it seems plausible that T cells might be equipped with a more efficient enzymatic machinery for metabolizing adenine dinucleotides compared with HEK-293 cells. This would also explain why T cell currents are already enhanced relative to HEK-293 cells even in K+-based solutions.
To test the above hypothesis, we performed two types of experiments. We first confirmed that the synergy between cADPR and ADPR previously observed in heterologously expressed TRPM2 also applies to native IADPR by co-applying subthreshold concentrations of cADPR (30 µM) and ADPR (5 µM) using K+-based pipette solutions in T cells. At these subthreshold concentrations, neither of the agonists applied alone would activate IADPR. However, their combined presence resulted in full activation of IADPR currents that were significantly larger than those obtained by 1 mM cADPR alone (Fig. 2G
). In a second set of experiments, we determined whether the full activation of IADPR induced by a high concentration of cADPR alone (1 mM) in a Cs+-based pipette solution was in part due to endogenous ADPR mobilization. We took advantage of AMP, which we have previously shown to inhibit ADPR—but not cADPR—mediated gating of TRPM2. Also, we reasoned that if ADPR contributed to the cADPR response, AMP should prevent the full activation. As illustrated in Fig. 2H
, AMP indeed prevented the full activation of cADPR-induced IADPR, leaving only a small current that presumably reflects the direct gating of TRPM2 by cADPR. This finding suggests that T cells indeed produce significant ADPR levels from cADPR and the combined presence of both agonists fully activates TRPM2 channels. In HEK-293 cells, the mobilization of ADPR in K+-based solutions may not be sufficient to trigger full activation, whereas Cs+ might just be able to mobilize enough ADPR to cause the synergistic activation.
Our finding that cADPR activates IADPR currents has important implications for cADPR function. Most studies demonstrate that cADPR acts through the ryanodine receptor to release Ca2+ from internal stores. There is, however, some indication that cADPR may also play a role in calcium entry in some cell types. The first report to suggest that cADPR may gate a cation channel came from ascidian oocytes, where ADPR was identified as the primary gating mechanism for an ion channel that triggers the fertilization response and cADPR was also found to be effective (28)
. The properties of that ion channel, however, are quite different from of TRPM2. More directly relevant to the context of the current study is the fact that cADPR was found to induce Ca2+ influx in T cells by producing spikes of [Ca2+]i over long time periods that were dependent on the presence of extracellular Ca2+ (20)
. Since TRPM2 was unknown at that time, this calcium entry was not attributed to calcium influx through any particular ion channel. cADPR also appears to be required for sustained extracellular Ca2+ influx in neutrophils that have been stimulated by the bacterial chemoattractant, formyl-methionyl-leucyl-phenylalanine (fMLP), since the sustained Ca2+ influx phase of neutrophils derived from transgenic mice that lack the ADP-ribosyl cyclase CD38 is greatly reduced (22)
. The data presented here show that cADPR may in fact directly gate a plasma membrane ion channel in support of Ca2+ influx and may underlie the cADPR-mediated Ca2+ influx observed in these cell types.
More recently, a new Ca2+-mobilizing messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), has emerged (18
, 23
24
25)
. Like cADPR, NAADP can be produced via CD38 and like cADPR it appears to cause both Ca2+ release and Ca2+ influx, although there is currently no consensus on whether NAADP targets the same receptor as cADPR. We considered the possibility that NAADP might affect TRPM2 channels and perfused HEK-293 cells expressing TRPM2 with various concentrations of this putative second messenger. NAADP indeed activated TRPM2 currents (Fig. 3
A) with a typical linear current-voltage relationship (Fig. 3B
) and in a dose-dependent manner with an EC50 for of 730 µM (Fig. 3C
). We confirmed that NAADP could also activate IADPR in Jurkat T cells (Fig. 3D
) and proceeded to characterize the NAADP mechanism in HEK-293 cells.
|
Since the efficacy of NAADP in activating TRPM2 was similar to that of cADPR, we reasoned that it might also synergize with ADPR at significantly lower concentrations. Indeed, when co-perfusing cells with subthreshold concentrations of either nt (100 µM NAADP+3 µM ADPR), we obtained full activation of TRPM2 (Fig. 4
A). Under these experimental conditions, AMP fully suppressed current activation, confirming that NAADP sensitized TRPM2 gating by ADPR. This prompted us to test whether the NAADP mechanism was related to the one we demonstrated earlier for cADPR. We included the cADPR antagonist 8-Br-cADPR (100 µM), and this too inhibited the response to the co-applied NAADP and ADPR (Fig. 4A
). This clearly suggests that NAADP is an integral part of the response and additionally suggests that its mechanism of action and binding site is the same as that for cADPR.
|
In light of the synergy between NAADP and ADPR, we asked whether the current activation seen with NAADP alone was entirely due to NAADP or contained an ADPR component that could arise from ADPR mobilization. Fig. 4B
demonstrates that the full TRPM2 activation by NAADP could be suppressed by both AMP and 8-Br-cADPR and Fig. 4C
illustrates the remaining currents at higher resolution. It can be seen that AMP leaves a small remaining current, whereas 8-Br-cADPR causes a complete block of the current. This finding is consistent with the interpretation that NAADP, like cADPR, has some limited ability to gate TRPM2 directly even when the ADPR component is suppressed by AMP, whereas a direct antagonist like 8-Br-cADPR removes this effect as well.
DISCUSSION
Our results indicate that TRPM2, a Ca2+-permeable nonselective cation channel natively expressed in lymphocytes, can be gated by ADPR and cADPR. This gating can be observed in both whole-cell experiments, as well as in cell-free inside-out experiments indicating that both ADPR and cADPR act directly on the TRPM2 channel. We further demonstrate that NAADP acts in a very similar manner as cADPR in that it possesses a limited ability to gate TRPM2 directly, but strongly potentiates ADPR-mediated activation of the channel. An important observation in support of a synergy between cADPR and NAADP with ADPR is that intracellular administration of cADPR or NAADP apparently is accompanied by elevated levels of ADPR, which is further increased when using Cs+-based intracellular solutions. At this point, we cannot ascribe this ADPR mobilization to a particular mechanism. The simplest explanation, that the nucleotides are metabolized to ADPR, faces the paradox that the best-characterized enzyme that could convert cADPR to ADPR, CD38, is an ectoenzyme and, therefore, not an obvious candidate to mediate this conversion. It is conceivable that other cytosolic enzymes yet to be characterized may be responsible for this phenomenon. Another explanation, that ADPR might be released from intracellular compartments, also cannot be readily explained, since the major store for ADPR is presumed to be mitochondrial and its possible release via cADPR or NAADP has not yet been documented.
Our findings raise a number of important questions regarding the specificity and the physiological function of cADPR and NAADP. We consider the effects of these nucleotides to be specific, since other nucleotides fail to activate TRPM2 even at high concentrations (2)
. Specificity is also evident from the fact that the cADPR antagonist 8-Br-cADPR completely blocks both cADPR- and NAADP-mediated gating of TRPM2, which suggests that both agonists access the same binding site on TRPM2. This binding site is clearly distinct from that of ADPR, since 8-Br-cADPR does not affect the activation by ADPR. Conversely, the direct activation of TRPM2 by cADPR and NAADP, albeit limited, cannot be suppressed by the specific ADPR antagonist AMP.
Another important question relates to the potency and physiological significance of cADPR- and NAADP-mediated activation of TRPM2, which occurs at relatively high concentrations of the second messengers; considerably higher than the nanomolar levels required to activate Ca2+ release. First, the nucleotide concentrations needed to activate TRPM2 in our patch-clamp experiments may not necessarily reflect the effective concentrations required to gate TRPM2 in intact cells. The differences we observed with K+- and Cs+-based pipette solutions attest to the fact that the intracellular environment does affect the sensitivity of TRPM2 and this is inevitably perturbed by whole-cell perfusion. Second, although recent evidence obtained in pancreatic acinar cells indicates that the receptor agonist cholecystokinin (CCK) can rapidly produce transient increases in NAADP and both CCK and acetylcholine can generate long-lasting increases in intracellular cADPR levels (27)
, there is no detailed knowledge about the global cytosolic or local subplasmalemmal concentrations that are achieved under specific physiological conditions. So far, only one study has assessed NAADP concentrations and arrived at low micromolar levels in sea urchin eggs (29)
. Higher levels of NAADP might occur under some pathological conditions caused, e.g., by enhanced activity of enzymes that generate NADP or by reduced activity of enzymes that metabolize it. It is conceivable that cADPR and NAADP can have a dual mode of action in that low concentrations can trigger Ca2+ release and higher concentrations additionally recruit TRPM2. Although highly speculative, it is even possible that TRPM2 might be expressed in intracellular compartments and also serve as a release channel, where it may have a different sensitivity toward cADPR/NAADP, possibly due to being exposed to an intraorganellar acidic environment. Such a dual function of release activity and Ca2+ influx across the plasma membrane is not without precedent, as it has been demonstrated for the vanilloid receptor VR1 (30)
. Our present demonstration that cADPR and NAADP share a common target in activating TRPM2 might also indicate a common target that mediates their Ca2+ release activity regardless of whether the release activity is or is not mediated by TRPM2. Our present knowledge only allows us to conclude that if we accept cADPR and NAADP as genuine and relevant activators of TRPM2 either in the plasma membrane or in Ca2+ stores, then we must assume that these messengers are in fact produced at the relevant concentrations needed to do so. Finally, cADPR and NAADP may not represent primary or singular activators of TRPM2, but rather synergistic co-activators. It is likely that these messengers are produced along with additional factors that could significantly shift the sensitivity of TRPM2 toward them. One such factor is [Ca2+]i, and there could be other signaling pathways that synergize with [Ca2+]i and ADPR/cADPR/NAADP to enable TRPM2 gating at concentrations that are achieved physiologically.
ACKNOWLEDGMENTS
We thank Mahealani K. Monteilh-Zoller and Ka’ohimanu L. Dang for expert technical assistance. This work was supported in part by the following grants from the National Institutes of Health: R01-NS40927, R01-AI50200 and R01-GM 063954 to R.P. and R01-GM 65360 to A.F.
FOOTNOTES
1 These authors contributed equally to this work. 
Received for publication November 28, 2005. Accepted for publication December 28, 2005.
REFERENCES
This article has been cited by other articles:
|
|
 |
|
  B. Buelow, Y. Song, and A. M. Scharenberg The Poly(ADP-ribose) Polymerase PARP-1 Is Required for Oxidative Stress-induced TRPM2 Activation in Lymphocytes J. Biol. Chem., September 5, 2008; 283(36): 24571 - 24583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Malavasi, S. Deaglio, A. Funaro, E. Ferrero, A. L. Horenstein, E. Ortolan, T. Vaisitti, and S. Aydin Evolution and Function of the ADP Ribosyl Cyclase/CD38 Gene Family in Physiology and Pathology Physiol Rev, July 1, 2008; 88(3): 841 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Dietrich and T. Gudermann Another TRP to Endothelial Dysfunction: TRPM2 and Endothelial Permeability Circ. Res., February 15, 2008; 102(3): 275 - 277. [Full Text] [PDF]
|
|
|
|
|
|
C. M. Hecquet, G. U. Ahmmed, S. M. Vogel, and A. B. Malik Role of TRPM2 Channel in Mediating H2O2-Induced Ca2+ Entry and Endothelial Hyperpermeability Circ. Res., February 15, 2008; 102(3): 347 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Sieck, T. A. White, M. A. Thompson, C. M. Pabelick, M. E. Wylam, and Y. S. Prakash Regulation of store-operated Ca2+ entry by CD38 in human airway smooth muscle Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L378 - L385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Partida-Sanchez, A. Gasser, R. Fliegert, C. C. Siebrands, W. Dammermann, G. Shi, B. J. Mousseau, A. Sumoza-Toledo, H. Bhagat, T. F. Walseth, et al. Chemotaxis of Mouse Bone Marrow Neutrophils and Dendritic Cells Is Controlled by ADP-Ribose, the Major Product Generated by the CD38 Enzyme Reaction J. Immunol., December 1, 2007; 179(11): 7827 - 7839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Shi, S. Partida-Sanchez, R. S. Misra, M. Tighe, M. T. Borchers, J. J. Lee, M. I. Simon, and F. E. Lund Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes J. Exp. Med., October 29, 2007; 204(11): 2705 - 2718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-C. Chang, J. Di Capite, C. Nelson, and A. B. Parekh All-or-None Activation of CRAC Channels by Agonist Elicits Graded Responses in Populations of Mast Cells J. Immunol., October 15, 2007; 179(8): 5255 - 5263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Starkus, A. Beck, A. Fleig, and R. Penner Regulation of TRPM2 by Extra- and Intracellular Calcium J. Gen. Physiol., September 24, 2007; 130(4): 427 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Graeff, Q. Liu, I. A. Kriksunov, Q. Hao, and H. C. Lee Acidic Residues at the Active Sites of CD38 and ADP-ribosyl Cyclase Determine Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Synthesis and Hydrolysis Activities J. Biol. Chem., September 29, 2006; 281(39): 28951 - 28957. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
