ライフサイエンスコーパス: NAADP

1 NAADP binds to specific, high-affinity membrane binding

2 NAADP is a potent second messenger that mobilizes Ca(2+)

3 NAADP is thus a potential antidiabetic agent with therap

4 NAADP plays an important role in calcium signalling in t

5 NAADP released Ca2+ from the same thapsigargin-sensitive

6 NAADP triggered heterogeneous local Ca(2+) signals, incl

7 NAADP uptake was inhibitable by Ned-19, a NAADP mimic; d

8 NAADP was shown to evoke functionally relevant Ca(2+) si

9 NAADP-AM failed to enhance Ca(2+) responses in cardiac m

10 NAADP-regulated Ca(2+) release channels, likely two-pore

11 -enzyme 2'-NADP and the calcium mobilizer 2'-NAADP.

12 ation by [Ca(2+)](i), cyclic ADPR, H(2)O(2), NAADP, and negative feedback regulation by AMP and perme

13 Interestingly, 3'-NADP and 3'-NAADP have previously been used as inhibitors or signali

14 inic acid adenine dinucleotide phosphate (3'-NAADP), are substantially different from the ubiquitous

15 s (HEK293, SKBR3), and mouse pancreas, 5N(3)-NAADP selectively labeled low molecular weight sites tha

16 r concentrations of unlabeled NAADP or 5N(3)-NAADP, but not by micromolar concentrations of structura

17 [(32)P-5N(3)]NAADP binding was saturable and displayed high affinity

18 The proteins photolabeled by [(32)P-5N(3)]NAADP have molecular masses smaller than the sea urchin

19 [(32)P-5N(3)]NAADP photolabeling was irreversible in a high K(+) buff

20 g homogenates preincubated with [(32)P-5N(3)]NAADP resulted in specific labeling of 45-, 40-, and 30-

21 adenine dinucleotide phosphate ([(32)P-5N(3)]NAADP) as a photoaffinity probe.

22 toprobe based on 5-azido-NAADP ([(32)P-5N(3)]NAADP) that exhibits high affinity binding to NAADP rece

23 NAADP uptake was inhibitable by Ned-19, a NAADP mimic; dipyridamole, a nucleoside inhibitor; or Na

24 he first time provide direct evidence that a NAADP-sensitive Ca2+ release channel is present in the l

25 w that the loss of endogenous TPCs abolished NAADP-dependent Ca(2+) responses as assessed by single-c

26 ndent NAADP synthesis; second, by activating NAADP-regulated channels.

27 These data suggest that high affinity NAADP binding sites are distinct from TPCs.

28 Furthermore, labeling of high affinity NAADP binding sites was preserved in pancreatic samples

29 branes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca(2+) r

30 Upon activation, an NAADP/SERCA3 Ca(2+) mobilization pathway initiates an ea

31 ing high potency and agonist efficacy and an NAADP derivative substituted at both the 5-position of t

32 rove that it is a pore-forming subunit of an NAADP-gated Ca(2+) channel.

33 We conclude that an NAADP increase plays a physiologically relevant role dur

34 base-exchange reactions to produce ADPR and NAADP(+).

35 osphate (AMP), which suggests that cADPR and NAADP lead to mobilization of endogenous ADPR presumably

36 by 8-Br-cADPR, which suggests that cADPR and NAADP share a common binding site on TRPM2 that can regu

37 syl cyclase inhibitor that reduces cADPR and NAADP synthesis in mouse membrane fractions, was shown t

38 We conclude that cADPR and NAADP, in combination with ADPR, represent physiological

39 The present study documents that TPC1 and NAADP-binding sites showed a colocalization at the acros

40 ss any AP isoenzymes and did not display any NAADP 2'-phosphatase activity.

41 nels (TPCs) have been recently identified as NAADP-regulated Ca(2+) release channels, which are local

42 ls (TPCs) within the endolysosomal system as NAADP-regulated Ca(2+) channels that release organellar

43 by anti-TRP-ML1 antibody markedly attenuated NAADP-induced activation of these lysosomal Ca2+ channel

44 ng a radioactive photoprobe based on 5-azido-NAADP ([(32)P-5N(3)]NAADP) that exhibits high affinity b

45 5-Azido-NAADP was shown to release calcium from sea urchin egg h

46 5-(3-Azidopropyl)-NAADP was shown to release Ca(2+) with an EC50 of 31 muM

47 Interplay between NAADP receptors and more established intracellular Ca(2+

48 arger TPC complex is responsible for binding NAADP that is unique from the core channel itself.

49 cyclase family, catalyzes synthesis of both NAADP and cADPR in vitro However, it remains unclear whe

50 al exocytosis supports the concept that both NAADP-gated cascades match local NAADP concentrations wi

51 trolled Mg(2+), TPC2 is readily activated by NAADP with channel properties identical to those in resp

52 although both TPC1 and TPC2 are activated by NAADP, TPC1 appears to be additionally regulated by cyto

53 ated by PI(3,5)P(2) and are not activated by NAADP.

54 d recombinant TPC1 channels are activated by NAADP.

55 els (TPCs) and their potential activation by NAADP.

56 e also the acidic Ca(2+) stores mobilized by NAADP via TPC channels on the granules themselves, so th

57 ted channels regulated by mTORC1, but not by NAADP.

58 er Ca(2+) released from acidic organelles by NAADP subsequently recruits IP3 or ryanodine receptors o

59 (TPCs) have been proposed to be regulated by NAADP, recent studies have challenged this.

60 endolysosomal channels that are regulated by NAADP; however, the nature of the NAADP receptor binding

61 The molecular basis for calcium release by NAADP, however, is not clear and subject to controversy.

62 The molecular basis for Ca(2+) release by NAADP, however, is uncertain.

63 ive pore region abrogated calcium release by NAADP.

64 ture of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors

65 he identity of the Ca(2+) stores targeted by NAADP in conventional naive T cells is less clear.

66 In Tpcn1/2(-/-) cells, NAADP sensitivity was restored by re-expressing wild-typ

67 In cell-free extracts of HeLa cells, NAADP was degraded to nicotinic acid adenine dinucleotid

68 Fifth, tracheal homogenates contained NAADP-binding sites of high affinity.

69 Our finding that two convergent NAADP-dependent pathways are operative in driving acroso

70 little is known about the mechanism coupling NAADP binding to calcium release.

71 ways: first, by stimulating Ca(2+)-dependent NAADP synthesis; second, by activating NAADP-regulated c

72 a rapid and transient increase in endogenous NAADP levels.

73 ly, glucose stimulation increases endogenous NAADP levels, providing strong evidence for recruitment

74 e, we demonstrate the presence of endogenous NAADP in HeLa cells.

75 PML1(D471K) was without affect on endogenous NAADP-mediated Ca(2+) signals.

76 dic-like Ca(2+) stores via the endolysosomal NAADP-sensitive two-pore channels.

77 Whereas overexpression of TPCs enhanced NAADP-mediated Ca(2+) signals, overexpression of TRPML1

78 of two-pore channel (TPC) proteins enhances NAADP-induced Ca(2+) release, whereas the NAADP response

79 ere, we show that NAADP acetoxymethyl ester (NAADP-AM), a cell-permeant NAADP analog, increases cytos

80 and nicotinic acid and metabolize exogenous NAADP to nicotinic acid adenine dinucleotide by a 2'-pho

81 us provides a potential mechanism to explain NAADP-induced Ca(2+) oscillations.

82 Finally, NAADP-evoked Ca(2+) oscillations in pancreatic acinar ce

83 AP isoform emerged as the best candidate for NAADP degradation in HeLa cells.

84 ely the long sought after target channel for NAADP.

85 re the long sought after target channels for NAADP.

86 Thus, TPC1 is critical for NAADP action and is likely the long sought after target

87 The trigger hypothesis for NAADP action proposes that calcium release from acidic s

88 Ca(2+)-permeable channels indispensable for NAADP signalling.

89 The degradation pathway for NAADP is unknown and no enzyme that can specifically hyd

90 summary, our observations define a role for NAADP and TPC2 at lysosomal/sarcoplasmic reticulum junct

91 Here, we report a new role for NAADP in arrhythmogenic Ca(2+) release in cardiac myocyt

92 e Ca2+ stores in PC12 cells, (ii) a role for NAADP in differentiation, and (iii) that Ca2+-dependent

93 This study highlights a selective role for NAADP in stimulating exocytosis crucial for immune cell

94 uctures and dynamics, implicating a role for NAADP in the regulation of vesicular trafficking.

95 d that TPCs, not TRPMLs, are the targets for NAADP.

96 Both have been proposed as targets for NAADP.

97 increases the apparent affinity of TPC1 for NAADP by 10 nm/mV.

98 mprise a highly specialized trigger zone for NAADP-dependent Ca(2+) signaling by the vasoconstrictor

99 Thus, TPCs form NAADP receptors that release Ca(2+) from acidic organell

100 is the first report demonstrating functional NAADP receptors in a mammalian neuron.

101 Furthermore, NAADP was found to be released from pancreatic islets up

102 re we show that CD38 can, in fact, hydrolyze NAADP to ADP-ribose 2'-phosphate.

103 Our findings implicate NAADP-evoked Ca(2+) release from acidic Ca(2+) storage o

104 Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol

105 Importantly, NAADP at physiological concentrations (50-100 nM) was de

106 omiscuous enzyme described to be involved in NAADP metabolism, was not detectable in HeLa cells.

107 iculty of catching a small transient rise in NAADP levels.

108 Our data affirm a key role for TPC2 in NAADP-mediated Ca(2+) signaling and link this pathway to

109 s with saponin and/or Triton X-100 increased NAADP synthesis, indicating that intracellular CD38 cont

110 renoreceptor signaling in the heart involves NAADP and lysosomes.

111 Here we provide details of how to isolate NAADP from cells by extraction with perchloric acid and

112 ffinity for activation of TPC1 by its ligand NAADP is not constant.

113 t that both NAADP-gated cascades match local NAADP concentrations with the efflux of acrosomal calciu

114 reconstituted and characterized a lysosomal NAADP-sensitive Ca2+ release channel using purified lyso

115 Furthermore, the identity of lysosomal NAADP-sensitive Ca2+ release channels was also investiga

116 nterestingly, the activity of this lysosomal NAADP-sensitive Ca2+ release channel increased when the

117 refined and improved a method for measuring NAADP levels and presented it in a manner accessible to

118 Thus, TPC1 and TPC2 both mediate NAADP-induced Ca(2+) release, but the subsequent amplifi

119 rms localize to acidic organelles to mediate NAADP-dependent calcium release.

120 In vitro, CD38-mediated NAADP synthesis requires an acidic pH and a nonphysiolog

121 iated mechanism, but the mechanism mediating NAADP-induced intracellular Ca2+ release remains unclear

122 maR activation recruits the second messenger NAADP and thereby promotes the opening of Ca(2+) -permea

123 The second messenger NAADP triggers Ca(2+) release from endo-lysosomes.

124 Hence, the second messenger NAADP, promoting efflux of calcium from lysosome-like co

125 mirrored by the Ca(2+)-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P(2), respectivel

126 Moreover, the NADP(+) metabolite, NAADP(+), regulates intracellular calcium homeostasis vi

127 ma in either the nanomolar or low micromolar NAADP concentration range, where TPC1 was found to be re

128 Moreover, NAADP activates TPCs to drive exocytosis in a way that i

129 However, whether TPCs constitute native NAADP receptors is unclear.

130 Notably, NAADP-mediated Ca(2+) release in intact cells is regulat

131 for the first time (i) the presence of novel NAADP-sensitive Ca2+ stores in PC12 cells, (ii) a role f

132 t of charged groups to the nicotinic acid of NAADP is associated with loss of activity, suggesting th

133 n kinase II inhibitors suppressed actions of NAADP in myocytes.

134 Our data extend the actions of NAADP to the endothelium both in vitro and in vivo, poin

135 Consistently, administration of NAADP to type 2 diabetic mice improved glucose tolerance

136 , we show that intravenous administration of NAADP-AM into anesthetized rats decreases mean arterial

137 Extracellular application of NAADP has been shown to elicit intracellular Ca(2+) sign

138 hannels (TPC), a recently described class of NAADP- and PI(3,5)P2-sensitive Ca(2+)-permeable cation c

139 We demonstrate that liposomal delivery of NAADP mediated release of Ca2+ from acidic Ca2+ stores a

140 onsible for controlling the pH dependence of NAADP synthesis by the cyclase.

141 say is highly selective for the detection of NAADP under cell extract conditions.

142 M to 1 microM, but this activating effect of NAADP was significantly reduced when the concentrations

143 ryanodine receptors abolished the effects of NAADP on neurite length and reduced the magnitude of NAA

144 vidence for AP as the metabolizing enzyme of NAADP in cells that do not express CD38.

145 wo-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 (also known as TPCN1) a

146 in a high K(+) buffer, a hallmark feature of NAADP binding in the egg system.

147 key to the investigation of the functions of NAADP as a Ca2+ -releasing second messenger.

148 These observations support generation of NAADP and cADPR by intracellular CD38, which contributes

149 base-exchange reaction in the generation of NAADP.

150 rent study, we demonstrate the importance of NAADP in the generation of Ca(2+) signals in murine naiv

151 Infusion of NAADP into intact cardiac myocytes induced global Ca(2+)

152 Selective pharmacological inhibition of NAADP-evoked Ca(2+) release or genetic ablation of endol

153 ores, supporting emerging interpretations of NAADP physiology and pharmacology in heart.

154 nist Ned-19, we addressed the involvement of NAADP in the generation of Ca(2+) signals evoked by TCR

155 neurite length and reduced the magnitude of NAADP-mediated Ca(2+) signals.

156 thod to prevent the endogenous metabolism of NAADP by chelating Ca2+ with bis-(o-aminophenoxy)ethane-

157 Microinjection of NAADP mimicked the fertilization cortical response, sugg

158 tes critical evaluation of current models of NAADP-triggered activation of the TPC family.

159 hat exhibited the diagnostic pharmacology of NAADP-sensitive Ca(2+) release.

160 be introduced at the 8-adenosyl position of NAADP while preserving high potency and agonist efficacy

161 urthermore, the single channel properties of NAADP-activated TPC2delN were not affected by TRPML1.

162 HEK293 cells, resulting in reconstitution of NAADP 2'-phosphatase activity in cell-free extracts.

163 anelles, using organelle pH as a reporter of NAADP action.

164 In contrast, the role of NAADP in Ca(2+) signaling or the identity of the Ca(2+)

165 a basis for the recently-discovered role of NAADP in reperfusion-induced cell death.

166 r understanding of the physiological role of NAADP.

167 discovered that CD38 catalyzes synthesis of NAADP by exchanging the nicotinamide moiety of nicotinam

168 Synthesis of NAADP catalyzed by CD38 is known to have strong preferen

169 r Ca(2+) channels are the primary targets of NAADP.

170 omes and sarcoplasmic reticulum dependent on NAADP and TPC2 comprise an important element in beta-adr

171 the second messengers IP3 and cADPR (ER) or NAADP (acidic organelles).

172 Overall, NAADP exhibited a similar profile in mediating Ca(2+) re

173 High-affinity [(32)P]NAADP binding still occurs in Tpcn1/2(-/-) tissue, sugge

174 low concentration and to compete with [(32)P]NAADP in a competition ligand binding assay with an IC(5

175 mpetition ligand binding assays using [(32)P]NAADP.

176 reciprocally both are stimulated by permeant NAADP.

177 toxymethyl ester (NAADP-AM), a cell-permeant NAADP analog, increases cytosolic Ca(2+) concentration i

178 Application of membrane-permeant NAADP acetoxymethyl ester to PASMCs elicited a biphasic

179 cotinic acid adenine dinucleotide phosphate (NAADP(+)), both of which have been shown to modulate cal

180 nicotinamide adenine dinucleotide phosphate (NAADP) and Ca(2+).

181 cotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR) are Ca(2+)-mobilizi

182 cotinic acid adenine dinucleotide phosphate (NAADP) and its recently identified molecular target, two

183 cotinic acid adenine dinucleotide phosphate (NAADP) antagonist BZ194 (200 mum) had no effect on eithe

184 cotinic acid adenine dinucleotide phosphate (NAADP) evokes highly localized intracellular Ca(2+) sign

185 cotinic acid adenine dinucleotide phosphate (NAADP) from NAD phosphate (NADP).

186 cotinic acid adenine dinucleotide phosphate (NAADP) in cell extracts using surface-enhanced Raman spe

187 cotinic acid adenine dinucleotide phosphate (NAADP) in the control of Ca(2+)-dependent functions.

188 cotinic acid adenine dinucleotide phosphate (NAADP) in the insulin-secreting beta-cell line MIN6.

189 cotinic acid adenine dinucleotide phosphate (NAADP) is a Ca(2+) releasing intracellular second messen

190 cotinic acid adenine dinucleotide phosphate (NAADP) is a messenger that regulates calcium release fro

191 cotinic acid adenine dinucleotide phosphate (NAADP) is a novel metabolite of NADP that has now been e

192 cotinic acid adenine dinucleotide phosphate (NAADP) is a potent and widespread calcium-mobilizing mes

193 cotinic acid adenine dinucleotide phosphate (NAADP) is a potent second messenger that mobilizes Ca(2+

194 cotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger for mobilizing Ca(2+) from

195 cotinic acid adenine dinucleotide phosphate (NAADP) is a ubiquitous messenger proposed to stimulate C

196 cotinic acid adenine dinucleotide phosphate (NAADP) is a ubiquitous second messenger providing a Ca(2

197 cotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing mes

198 cotinic acid adenine dinucleotide phosphate (NAADP) is an agonist-generated second messenger that rel

199 cotinic acid adenine dinucleotide phosphate (NAADP) is capable of inducing global Ca2+ increases via

200 cotinic acid adenine dinucleotide phosphate (NAADP) is increasingly being demonstrated to be involved

201 cotinic acid adenine dinucleotide phosphate (NAADP) is the least well understood in terms of its mole

202 cotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+) mobilizing second messe

203 cotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+)-mobilizing messenger th

204 cotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+)-releasing second messen

205 cotinic acid adenine dinucleotide phosphate (NAADP) levels in cells has been, and remains, key to the

206 cotinic acid adenine dinucleotide phosphate (NAADP) on neurite length and cytosolic Ca(2+) levels.

207 cotinic acid adenine dinucleotide phosphate (NAADP) potently releases Ca(2+) from acidic intracellula

208 cotinic acid adenine dinucleotide phosphate (NAADP) releases Ca(2+) from the acidic Ca(2+) stores of

209 cotinic Acid Adenine Dinucleotide Phosphate (NAADP) stimulates calcium release from acidic stores suc

210 cotinic acid adenine dinucleotide phosphate (NAADP) strongly activate natively expressed TRPM2 channe

211 cotinic acid adenine dinucleotide phosphate (NAADP) with substitution at either the 4- or the 5-posit

212 cotinic acid adenine dinucleotide phosphate (NAADP), a novel Ca2+-mobilizing messenger, with that of

213 cotinic acid adenine dinucleotide phosphate (NAADP), and the mammalian target of rapamycin (mTOR).

214 cotinic acid adenine-dinucleotide phosphate (NAADP), and the specific engagement of the two-pore chan

215 cotinic acid adenine dinucleotide phosphate (NAADP), the most potent Ca(2+) mobilizing second messeng

216 cotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca(2+) release in many diverse cell types.

217 cotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca(2+) release was also impaired using eit

218 cotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca(2+) release from intracellular stores

219 cotinic acid adenine dinucleotide phosphate (NAADP).

220 cotinic acid adenine dinucleotide phosphate (NAADP).

221 cotinic acid adenine dinucleotide phosphate (NAADP).

222 cotinic acid adenine dinucleotide-phosphate (NAADP), a potent calcium messenger, is able to trigger c

223 tinic acid adenosine dinucleotide-phosphate (NAADP): both Ca(2+) mobilization from SERCA3-dependent s

224 detect no requirement for cyclic ADP ribose, NAADP-dependent lysosomal Ca2+ release, activation of th

225 Second, NAADP increased cytosolic calcium in isolated cells when

226 With a SERS sensor, NAADP can be detected in less than 1 min without any spe

227 To further study NAADP binding sites, we have synthesized and characteriz

228 al systems that are widely used for studying NAADP-evoked Ca(2+) signaling, including sea urchin eggs

229 In contrast, several 5-substituted NAADP derivatives showed high potency for binding and fu

230 that these truncated proteins still support NAADP-induced Ca(2+) release.

231 WT but not CD38(-/-) mouse hearts supported NAADP and cADPR synthesis.

232 In contrast, TPC3 expression suppressed NAADP-induced Ca(2+) release.

233 Third, tracheal homogenates could synthesize NAADP by base exchange from exogenous NADP and nicotinic

234 Additionally, we demonstrate that NAADP dilates aortic rings in an endothelium- and NO-dep

235 Taken together, these data demonstrate that NAADP functions as a second messenger in tracheal smooth

236 We demonstrate that NAADP is neither generated nor broken down during sample

237 ides the first conclusive demonstration that NAADP is a genuine second messenger.

238 evolution and provide further evidence that NAADP mediates calcium release from acidic stores throug

239 We provide strong evidence that NAADP-mediated modulation of couplon activity plays a ro

240 It was found that NAADP activates lysosomal Ca2+ release channels at conce

241 We show here that NAADP-mediated Ca(2+) release from endolysosomal Ca(2+)

242 troversial, although evidence indicates that NAADP mobilizes Ca(2+) from lysosome-related acidic comp

243 We propose that NAADP is functioning as an autocrine/paracrine hormone i

244 We propose that NAADP regulates endolysosomal Ca(2+) storage and release

245 1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpre

246 We report that NAADP satisfies all five criteria as follows.

247 Here, we show that NAADP acetoxymethyl ester (NAADP-AM), a cell-permeant NA

248 Our data show that NAADP and physiological stimuli alter the pH within intr

249 sosomes to the plasma membrane and show that NAADP evokes Ca(2+) influx independent of ryanodine rece

250 Here we show that NAADP evokes localized Ca(2+) signals by mobilizing a ba

251 Here, we show that NAADP is effectively transported into selected cell type

252 Our results show that NAADP mediates complex global and local Ca(2+) signals.

253 We show that NAADP potentiates neurite extension in response to serum

254 We further show that NAADP-evoked Ca(2+) signals hyperpolarize endothelial ce

255 Recent studies showed that NAADP-induced Ca(2+) release is mediated by the two-pore

256 It has recently been shown that NAADP mediates Ca2+ mobilization by insulin in human pan

257 in intracellular organelles and suggest that NAADP signals through pH as well as Ca(2+).

258 curs in Tpcn1/2(-/-) tissue, suggesting that NAADP regulation is conferred by an accessory protein.

259 yanodine, or xestospongin C, suggesting that NAADP-mediated Ca(2+) signals interact with both ryanodi

260 The NAADP bolus plays a physiological role upon delivery to

261 Ca(2+) released from the ER can activate the NAADP pathway in two ways: first, by stimulating Ca(2+)-

262 However, the expression of TPCs and the NAADP-induced local Ca(2+) signals have not been examine

263 CA2b-dependent Ca(2+) stores pathway and the NAADP/SERCA3 pathway.

264 t of extracellular Ca(2+) and blocked by the NAADP antagonist Ned-19 or the vacuolar H(+)-ATPase inhi

265 emical analogue NADP and were blocked by the NAADP antagonist trans-Ned-19.

266 and primary ADP secretion are blocked by the NAADP receptor antagonist Ned-19, and reciprocally both

267 First, the NAADP antagonist Ned-19 inhibited contractions in trache

268 ermed TPC1 and TPC2, are responsible for the NAADP-mediated Ca(2+) release but the underlying mechani

269 To identify the NAADP binding site, we employed a photoaffinity labeling

270 ected that this will enhance research in the NAADP field.

271 l smooth muscle, and therefore, steps in the NAADP signaling pathway might provide possible new drug

272 on with perchloric acid and then measure the NAADP using a radioreceptor assay.

273 gulated by NAADP; however, the nature of the NAADP receptor binding site is unknown.

274 specific labeling and identification of the NAADP receptor.

275 d by NAADP and the molecular identity of the NAADP receptors remain controversial, although evidence

276 Hence, by virtue of the NAADP/TPC pathway, cytolytic granules generate Ca(2+) si

277 cellular pathway pharmacologically using the NAADP antagonist Ned-19 or genetically using Tpcn2(-/-)

278 ods and a pharmacological approach using the NAADP antagonist Ned-19, we addressed the involvement of

279 es NAADP-induced Ca(2+) release, whereas the NAADP response was abolished in pancreatic beta cells fr

280 osis and cytosolic pH but coincides with the NAADP-dependent fertilization Ca(2+) wave.

281 (SR) had no effect on the activity of these NAADP-activated Ca2+ release channels.

282 dulating effect on platelet activation, this NAADP-SERCA3 pathway may be a relevant target for anti-t

283 e is known about the functional role of this NAADP uptake system.

284 Thus, NAADP signaling appears an attractive novel target for a

285 Ca(2+) stores and ryanodine receptors and to NAADP antagonist BZ194.

286 possess the hallmark properties ascribed to NAADP receptors, including nanomolar ligand affinity [3-

287 AADP) that exhibits high affinity binding to NAADP receptors.

288 ating that intracellular CD38 contributes to NAADP production.

289 flash was eliminated in eggs desensitized to NAADP.

290 hat release organellar Ca(2+) in response to NAADP.

291 Responses to NAADP were abolished by disrupting the lysosomal proton

292 ere the Ca(2+) stores that were sensitive to NAADP in naive T cells.

293 h affinity NAADP binding, and TPC2 underpins NAADP-induced Ca(2+) release from lysosome-related store

294 ion of nanomolar concentrations of unlabeled NAADP or 5N(3)-NAADP, but not by micromolar concentratio

295 tes the egg by Ca(2+) release dependent upon NAADP, and accordingly, we report that fertilization als

296 These results demonstrate that a VEGFR2/NAADP/TPC2/Ca(2+) signaling pathway is critical for VEGF

297 To determine whether NAADP functions as a second messenger in tracheal smooth

298 ) with an EC50 of 31 muM and to compete with NAADP for receptor binding with an IC50 of 56 nM.

299 egion and that treatment of spermatozoa with NAADP resulted in a loss of the acrosomal vesicle that s

300 response, suggesting that it occurred within NAADP-sensitive acidic Ca(2+) stores.