Subcellular compartmentalization of CD38 in non hematopoietic cells a study to characterize its functional role in mitochondria 8

Chapter 5 Future Studies And Conclusions
216
CHAPTER 5
FUTURE STUDIES AND CONCLUSIONS

5.1 Summary of findings
The characteristic and functional analysis of mitochondrial CD38 was clearly
elucidated in the current study. Collectively, the results of this study propose that
intracellular localized CD38, i.e, mitochondrial CD38, could be involved in a central
mechanism in the regulation of intracellular Ca
2+
homeostasis, as oppose to another
topologically paradoxical alternative involving cell surface CD38.
The data presented in Chapter 3 showed that intracellular CD38 retains its
enzymatic functions, and support the specific association of CD38 with mitochondria.
In the study of using mouse brain tissues, data presented in Chapter 4 further
supported the conjecture that the long known mitochondrial NAD
+
glycohydrolase
could be in fact, the CD38 identified in this study. Its function in the mitochondria
may therefore involve coupling intracellular NAD
+
metabolism to cytosolic Ca
2+

signalling. This may bring about deeper insight into the complex signaling possibly
mediated by this molecule.

Functional role of mitochondrial CD38 was first determined by study on the
enzymatic activities of the molecule. Both intact mitochondria extracted from Mito-
CD38 transfected COS-7 cells and WT mouse brain tissues were capable of

cyclisation of NGD

to cGDPR, a fluorescent analog of cADPR (Chapter 3 Section
3.2.2 & Chapter 4 Section 4.2.4.1) as well as conversion of NAD
+
to ADPR (Chapter
4 Section 4.2.4.2). CD38 localized on mitochondria thus possessed typical ADP-
ribosyl cyclase activity as well as NAD
+
glycohydrolase activity. In agreement with
Chapter 5 Future Studies And Conclusions
217
reports that mitochondria are associated with abundant NAD
+
glycohydrolase activity,
it was noticed that total mitochondria fraction isolated from mouse brain tissues
showed both enzymatic activities with a significant higher ratio of NAD
+

glycohydrolase activity as compared to ADP-ribosyl cyclase activity (Chapter 4
Section 4.2.4.2). In view of the well established functional role of CD38, that is the
hydrolysis of NAD
+
to ADPR, and thus its major enzymatic property as a classic
NAD
+
glycohydrolase (Berthelier et al., 1998), data reported in this study was in
agreement with that reported by Aksoy et al. (2006). This group further showed
CD38 as the major regulator of in vivo NAD
+

levels in the brain tissues and
reaffirmed the presence of CD38 on mitochondria. There was no observation of any
cyclase activity from the isolated mitochondria fraction from CD38KO mouse brain
tissues (Chapter 4 Section 4.2.4) in the present study, thus the conclusion that all
cyclase activities observed were derived from CD38 found in mitochondria.
The localization of the enzymatically active CD38 in the mitochondria was
demonstrated in the present study to be specific to the outer mitochondrial membrane.
Topological studies with protease protection assay alone on intact
CD38
+
mitochondria (Chapter 3 Section 3.2.4) and protease protection assay
combined with digitonin titration assay on the Percoll purified intact mitochondria
extracted from mouse brain tissues (Chapter 4 Section 4.2.3) further confirmed the
localization of CD38 on the outer mitochondrial membrane. Moreover, the present
data suggested a specific topology for this mitochondrial CD38 with the enzyme’s
carboxyl catalytic site extruding to the cytosol region (Figure 5.1). This observation
was further supported by TEM and SEM results in Chapter 4 using antibodies that are
highly specific to CD38 and the staining patterns were compared against CD38 KO
mice samples. Having confirmed the location of CD38 on mitochondria, the
Chapter 5 Future Studies And Conclusions
218
functional role of this molecule was further investigated by a Ca
2+
release assay.
Indeed, the data presented demonstrated that the mitochondrial CD38 was able to
initiate the cADPR-sensitive Ca
2+
release mechanism in a well established ryanodine-
sensitive in vitro system (Chapter 3 Section 3.2.6). This specific location of CD38 on
mitochondria with a unique topology may provide a new perspective to the pathways

that might be associated with this enzyme. It is tempting to speculate that the
mitochondrial CD38 may serve as a vital molecule in regulating and mediating in
vivo NAD
+
level as well as important Ca
2+
signaling (Figure 5.2). Nevertheless, gaps
remain in the knowledge with regards to further defining the characteristic and
functional roles of mitochondrial CD38 for future studies.

5.2 Future studies
Lisa et al. (2001) reported that a majority of NAD
+
glycohydrolase activity
(~90%) is associated with rat heart mitochondria which located on the outer
mitochondria membrane. This group further showed that sarcolemmal rupture during
reperfusion injury of the heart results in exposure of the mitochondria to the
millimolar [Ca
2+
]
i
of the extracellular milieu. This in turn triggers the opening of the
PTP with the subsequent efflux of NAD
+
from the mitochondrial matrix which then
becomes available to NAD
+
glycohydrolase localized on outer mitochondria
membrane. It in turn results in the formation of Ca
2+

promoters such as cADPR,
NAADP and ADPR, which are known to trigger the release of Ca
2+
from the
intracellular Ca
2+
stores. It was hypothesized that a low density mitochondrial NAD
+

glycohydrolase which causes the mitochondrial hydrolysis of NAD
+
could eventually
induce an increase of intracellular [Ca
2+
]
i,
thus promoting further spreading of the
permeability transition to all mitochondria in the cell in a positive feedback loop. As a
Chapter 5 Future Studies And Conclusions
219
result, generalized mitochondrial dysfunction and irreversible contracture and
sarcolemmal rupture would follow. In combination with the present results, having
concluded that mitochondrial CD38 is an active enzyme which is capable of
catalyzing both ADP-ribosyl cyclase and NAD
+
glycohydrolase activities, it is
therefore interesting to determine whether the same process could apply to
mitochondrial CD38 observed in brain tissues (Figures 5.1 and 5.2). A simulated
post-ischemic/hypoxia model of brain in vitro system can be established as future
study to characterize the functional role (s) of brain mitochondrial CD38.

A study of CD38KO mice (Jin et al., 2007) was conducted and showed that
transmembrane CD38 has an essential role in regulating the secretion of oxytocin
(OT) via cADPR signaling pathways. However, it was observed that cADPR was
only effective at stimulating OT release in CD38 KO neuron terminals when the
tissue was permeabilised by digitonin as well as the availability of extracellular
NAD
+
. The group also observed that there was no increase of intracellular cADPR
when the intact cells were incubated with NAD
+
. Since there were no indication of
the presence of cADPR transporters on the respective OT and hypothalamic neurons,
therefore in order for CD38 to be involved in the OT secretion pathway, cADPR must
be present in the intracellular milieu. It was proposed that CD38 could act as the
transporter for transporting the cADPR to the intracellular region (Chapter 3
Introduction); the present data could also serve as an alternate model whereby
intracellular CD38 i.e, mitochondrial CD38 would fill in the missing link that bridges
CD38 and the intracellular cADPR-mediated calcium signalling in responsive cells.
Future study can be carried out to investigate this.
Generally most studies to date had focused on the ectocellular CD38
mechanism in cellular physiology. This study is the first to describe an expression of
Chapter 5 Future Studies And Conclusions
220
functional CD38 in a fully glycosylated form observed in mitochondria (Chapter 3),
which is further supported by results obtained from mouse brain mitochondria
(Chapter 4). It is not unreasonable to postulate that the locale of CD38 may be a key
factor in determining the specific function(s) it will perform in a particular site. It
would then be interesting to investigate the mechanism of the ubiquitous expression
of CD38 in different cellular compartments i.e, mitochondria, nucleus, ER. Two
possible areas could be ventured in order to explain this ubiquity. First, the molecule

may undergo post-translational modification and thus the isoforms are routed to
different locales in the cell. This is not without precedence. It was reported that
multiple IP
3
receptor isoforms have been shown to be present both on plasma
membrane and internal membranes (Quinton and Dean, 1996; Yule et al., 1997).
Second, significant data reported beginning in the 1990s indicate that lipid movement
between intracellular organelles can occur through contacts and close physical
association of membranes (Discussion of Chapter 3; Vance et al., 1991; Camici and
Corazzi, 1997).
Recent studies reporting the processing of human cytomegalovirus UL37
mutant glycoproteins in the endoplasmic reticulum (ER) lumen prior to mitochondrial
importation (Mavinakere et al., 2006), as well as observing mitochondrial and
secretory human cytomegalovirus UL37 proteins traffic into mitochondrion-
associated membranes (MAM) of human cells (Bozidis et al., 2008), further support
the above statements. Because of the well documented role of MAM trafficking
membrane-bound molecules from ER to mitochondria (Vance, 1991; Stone et al.,
2000; Ardail et al., 2003; Bionda et al., 2004) as well as taking in the consideration of
as a type II membrane glycoprotein, CD38 may subject to the ER-Golgi route; it is
then very tempting to speculate that CD38 would be shuttling between organelles via
Chapter 5 Future Studies And Conclusions
221
the membrane contact point, for example, the mitochondrion-associated membranes,
a subdomain of the ER acting as membrane bridges and thus provides direct physical
contact to mitochondria. It would be interesting to investigate the mechanism of the
shuttling of molecule between different cellular compartment as well as its specific
role involved in the particular locale.
It is interesting to note that liver mitochondrial CD38 has demonstrated a role
in NAADP sysnthesis, as observed by Liang et al. (1999). It was also reported that
the presence of specific NAADP binding sites in the brain on both neuronal and non-

neuronal cells (Bezin et al., 2006). In view of the results observed in current studies,
it would be interesting to investigate the synthesis of NAADP by brain mitochondrial
CD38 as well as its Ca
2+
mobilizing property, i.e, whether it can act in a similar
manner as cADPR. It was reported by Cancela et al. (1999) that pancreatic acinar
cells are more sensitive to NAADP than either cADPR and IP
3
with regard to agonist-
induced Ca
2+
-signaling. It remains to be seen if NAADP can have a role in brain
mitochondrial Ca
2+
signaling.
The next important question to be addressed regarding CD38-mediated
mitochondria Ca
2+
signaling is the mechanism involved in regulating the enzymatic
activities of mitochondrial CD38. A novel intracellular soluble ADP-ribosyl cyclase
can be regulated by tyrosine-phosphorylation, as reported by Guse et al., (1999). It
would therefore be tempting to investigate if similar mechanism applies to the
mitochondria CD38 as well, given that it has been reported that rat CD38 contains a
tyrosine residue in the cytoplasmic tail, which is conserved in mouse CD38 but not
human CD38 (Shubinsky and Schlesinger, 1997).
Moreover, it is interesting to note that recently published studies regarding
mitochondrial nitric oxide synthase (mtNOS) was observed in various tissues
Chapter 5 Future Studies And Conclusions
222
including rat and mouse brain, as discussed in the excellent review by Navarro and

Boveris (2008). Indeed, Nitric oxide has been shown to play a role in intracellular
Ca
2+
mobilization in sea urchin eggs via the cADPR-ribose signaling pathway
(Willmot et al., 1996). Nitric oxide activates a downstream signaling pathway in
which cADPR produced from activated CD38 mobilize cADPR-sensitive Ca
2+
stores
as well as regulate the ADP-ribosylation of various proteins (Zoche and Koch, 1995)
and the ADP-ribosyl cyclase activity of CD38 via S-nitrosylation (White et al., 2002).
mtNOS, which was reported to be localized at inner mitochondria membrane facing
the intermembrane space, may be in close proximity to the outer mitochondrial
membrane located CD38. This close apposition between the two molecules may have
specific role against each other. The roles of nitric oxide in the enzyme regulation
such as the autoribosylation of CD38 or regulation of the ADP-ribosylation of other
proteins via ADP-ribosyl transferase activity of CD38 are therefore interesting areas
to be determined and explored.

5.3 Concluding remarks
Mitochondrial CD38 was first reported by Liang et al. (1999) using rat liver
tissues, though the reports of mitochondrial NAD
+
glycohydrolase in rat brain and
liver tissues has long been established in 1980s (Discussion of Chapter 4). The
enzyme was identified by its subcellular localization in mitochondria and
immunoreaction towards anti-CD38 antibodies that recognize the cell surface CD38,
nucleus CD38 as well as microsomal CD38 on both rat and human brain samples
(Mizuguchi et al., 1995; Yamada et al., 1997). More reports surfaced on CD38
localized in mitochondria mouse brain tissues (Aksoy et al., 2006) as well as different
tissues such as pancreatic acinar cells (Sternfeld et al., 2003). It is hard to attribute

Chapter 5 Future Studies And Conclusions
223
CD38 in mitochondria to contamination from other cellular compartments because it
would seem unreasonable that very different tissues/ tissues from different species
would show a similar level of “contamination” of the mitochondrial fraction with the
membrane associated CD38. Hence the observations made in the current studies
begin to shed new light on the role and involvement of CD38 in the complexities of
mitochondrial signalling.
In conclusion, the current study proposes that signaling through mitochondrial
CD38 might represent a novel paradigm in cellular signaling processes, and is unique
in the sense that in addition to extracellular signaling, it is also involved in
intracellular signaling. This is particularly interesting in which mitochondria are
known as central to intracellular Ca
2+
homeostasis, steroid synthesis, generation of
free radical species, and apoptotic cell death. As a consequence, mitochondrial
dysfunction has devastating effects on the integrity of cells and may thus be critically
involved in aging, metabolic and degenerative diseases, as well as cancer in higher
organisms and humans (Wallace, 2005). Indeed the results of the current study give
us a new platform with which to re-visit and re-evaluate the current dogma on the
limits of this unusual molecule. While CD38 has long been regarded to be primarily
involved in surface membrane signaling events, the revelation of its presence on
mitochondria and the promise of the various roles it may play in mitochondrial
processes suggest to us that there is still much to learn from this fascinating molecule.
Chapter 5 Future Studies And Conclusions
224

Figure 5.1 Schematic representations of the proposed model of structure and
characteristic of CD38 located on mitochondria. Mitochondrial CD38 localized on the
outer mitochondrial membrane with a specific topology of its bulky carboxyl catalytic
domain extruding into the cytosol. In response to Ca
2+
, atractyloside, adenine
nucleotide depletion, chemotherapeutics and pro-oxidant agents, the mitochondrial
membrane permeabilization can result from the opening of PTP as a large unspecific
channel and leads to the release of proapoptotic factors into the cytosol. Following the
release of intramitochondrial NAD

+
to the cytosol, the immediate NAD
+
source
becomes substrate to CD38 located on the outer mitochondrial membrane. Ca
2+

mobilizing agents, cADPR and ADPR are generated which are in turn responsible for
the downstream signaling (Modified from Ayub and Hellett, 2004).

PTP

NAD
+

cADPR
ADPR
CD38
Permeability transition pore
IMM

OMM

Chapter 5 Future Studies And Conclusions
225

?

?

Extracellular region

Plasma membrane

NAD
+

Ca
2+

Ca
2+

uniporter
Na
+

/Ca
2+

exchanger
cADPR

Ca
2+

Endoplasmic reticulum

Mitochondria

Ryanodine

Receptor (RYR)

CD38

TRPM2

Permeability transition

pore
NAD
+

ADPR
Chapter 5 Future Studies And Conclusions
226

Figure 5.2 Proposed mechanisms for possible intracellular signaling mediated by
mitochondrial CD38. In response to rise in [Ca
2+
]
i
that promotes the opening of PTP
causing the release of intramitochondrial NAD
+
to the cytosol, this immediate NAD
+

source becomes substrate to CD38 located on the outer mitochondrial membrane.
Ca
2+
mobilizing agents, cADPR and ADPR are generated which are in turn
responsible for the downstream signaling as shown. In close proximity, RYR located
on endoplasmic reticulum is sensitive to activation under the action of cADPR.
Mitochondrial RYR was reported recently and the mechanism interplay with
mitochondrial CD38 waits to be explored further. Close apposition of mitochondria
and plasma membrane may give rise to an immediate source of ADPR which bind on
the TRPM2 cation channel located on the plasma membrane thus results in influx of
Ca
2+
and Na
+
from extracellular region (Ayub and Hellett, 2004).

Chapter 6 References
227
CHAPTER 6

REFERENCES

Aarhus R, Graeff RM, Dickey DM, Walseth TF and Lee HC (1995) ADP-ribosyl
cyclase and CD38 catalyze the synthesis of a calcium-mobilizing metabolite from
NADP. J Biol Chem 270:30327-30333.

Ardail D, Popa I, Bodennec J, Louisot P, Schmitt D and Portoukalian J (2003) The
mitochondria-associated endoplasmic-reticulum subcompartment (MAM fraction) of
rat liver contains highly active sphingolipid-specific glycosyltransferases. Biochem J
371:1013–1019.

Adebanjo OA, Anandatheerthavarada HK, Koval AP, Moonga BS, Biswas G, Sun L,
Sodam BR, Bevis PJ, Huang CL, Epstein S, Lai FA, Avadhani NG and Zaidi M
(1999) A new function for CD38/ADP-ribosyl cyclase in nuclear Ca
2+
homeostasis.
Nat Cell Biol 1:409-414.

Aiken C, Konner J, Landau NR, Lenburg ME and Trono D (1994) Nef induces CD4
endocytosis: requirement for a critical dileucine motif in the membrane-proximal
CD4 cytoplasmic domain. Cell 76:853-864.

Aktories K (1997) Rho proteins: targets for bacterial toxins. Trends Microbiol 5: 282-
288.

Aksoy P, White TA, Thompson M and Chini EN (2006) Regulation of intracellular
levels of NAD: A novel role for CD38. Biochem Biophys Res Comm 345:1386–1392.

Alessio M, Roggero S, Funaro A, De monte LB, Peruzzi L, Geuna M and Malavasi F
(1990) CD38 molecule: structural and biochemical analysis on human T

lymphocytes, thymocytes, and plasma cells. J Immunol 145:878-884.

Attardi G and Ching E (1979) Biogenesis of mitochondrial proteins in HeLa cells.
Methods Enzymol 56:66-79.

Ausiello CM, Urbani F, la Sala A, Funaro A and Malavasi F (1995) CD38 ligation
induces discrete cytokine mRNA expression in human cultured lymphocytes. Eur J
Immunol 25:1477-1480.

Ausiello CM, la Sala A, Ramoni C, Urbani F, Funaro A, Malavasi F (1996) Secretion
of IFN-gamma, IL-6, granulocyte-macrophage colony-stimulating factor and IL-10
cytokines after activation of human purified T lymphocytes upon CD38 ligation. Cell
Immunol 173: 192–197.

Ayub K and Hallett MB (2004) The mitochondrial ADPR link between Ca
2+
store
release and Ca
2+
influx channel opening in immune cells FASEB J 18:1335-1338.

Babakhanian K, Bendayan M and Bendayan R (2007) Localization of P-glycoprotein
at the nuclear envelope of rat brain cells. Biochem Biophys Res Comm 361:301-306.
Chapter 6 References
228

Barata H, Thompson M, Zielinska W, Han YS, Mantilla CB, Prakash YS, Feitoza S,
Sieck G and Chini EN (2004) The role of cyclic-ADP-ribose-signaling pathway in
oxytocin-induced Ca
2+

transients in human myometrium cells. Endocrinology 145:
881–889.

Barbosa MT, Soares SM, Novak CM, Sinclair D, Levine JA, Aksoy P, and Chini EN
(2007) The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the
development of diet-induced obesity. FASEB J 21: 3629–3639.

Barone F, Genazzani AA, Conti A, Churchill GC, Palombi F, Ziparo E, Sorrentino V,
Galione A and Filippine A (2002) A pivotal role for cADPR-mediated Ca
2+
signaling:
regulation of endothelin-induced contraction in peritubular smooth muscle cells.
FASEB J 16:697–705.

Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A. (2006) Resveratrol
improves health and survival of mice on a highcalorie diet. Nature 444: 337-42.

Beck A, Kolisek M, Bagley LA, Fleig A and Penner R (2006) Nicotinic acid adenine
dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T
lymphocytes. FASEB J 20: 962–964.

Becker RP and Sogard M (1979) Visualization of subsurface structures in cells and
tissues by backscattered electron imaging. Scanning Electron Microsc. 11:835-870.

Berger ER., Bercengren C and Person P (1974) On the morphological heterogeneity
of rat cardiac mitochondria. J. Cell Biol. 63: 22a.

Berger F, Lau C, Dahlmann M, and Ziegler M (2005) Subcellular compartmentation
and differential catalytic properties of the three human nicotinamide mononucleotide
adenylyltransferase isoforms. J Biol Chem 280: 36334–36341

Bellomo G, Jewell SA and Orrenius S (1982) The metabolism of menadione impairs
the ability of rat liver mitochondria to take up and retain calcium. J Biol Chem
257:11558-11562.

Bernardi P (1999) Mitochondrial Transport of Cations: Channels, Exchangers, and
Permeability Transition Physiol. Rev. 79: 1127–1155

Bernardi P and Azzone GF (1981) Cytochrome c as an electron shuttle between the
outer and inner mitochondrial membranes. J Biol Chem 256:7187–7192.

Berridge MJ (1998) Elementary and global aspects of calcium signalling. J Physiol
499:291-306.

Berthelier V, Tixier JM, Muller-Steener H, Schuber F and Deterre P (1998) Human
CD38 is an authentic NAD(P)
+
glycohydrolase. Biochem J 330:1383-1390.

Beutner G, Sharma VK, Giovannucci DR, Yule DI, Sheu SS (2001) Identification of
a ryanodine receptor in rat heart mitochondria. J Biol Chem 276: 21482-21488.
Chapter 6 References
229
Bezin S, Charpentier G, Fossier P and Cancela JM (2006) The Ca
2+
-releasing
messenger NAADP, a new player in the nervous system. J Physiol 99:111–118.

Billington RA, Travelli C, Ercolano E, Galli U, Roman CB, Grolla AA, Canonico PL,
Condorelli F and Genazzani AA (2008) Characterization of NAD uptake in

mammalian cells. J Biol Chem 283:6367-6374.

Bionda C, Portoukalian J, Schmitt D, Rodriguez-Lafrasse C and Ardail D (2004)
Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-
associated membrane) and/or mitochondria? Biochem J 382:527–533.

Bofill M, Mocroft A, Lipman M, Medina E, Borthwick NJ, Sabin CA, Timms A,
Winter M, Baptista L, Johnson MA, Lee CA, Phillips AN and Janossy G (1996)
Increased numbers of primed activated CD8
+
CD38
+
CD45RO
+
T cells predict the
decline of CD4
+
T cells in HIV-1-infected patients. AIDS 10:827-834.

Bolen JB (1993) Nonreceptor tyrosine protein kinases. Oncogene 8:2025-2031.

Boquist L (1984) Inhibition by dithioerythritol of alloxan induced efflux of Ca
2+
and
accompanying alterations in isolated liver mitochondria. Biochem Int 9:597-602.

Boyer CS, and Petersen DR (1991) The metabolism of 3, 7-dimethyl-2, 6-octadienal
(citral) in rat hepatic mitochondrial and cytosolic fractions. Interactions with aldehyde
and alcohol dehydrogenases. Drug Metab Dispos 19: 81-86

Boyer CS, Moor GA and Moldeus P (1993) Submitochondrial localization of the
NAD
+
glycohydrolase. J Biol Chem 268:4016-4020

Boyer CS, Neve EPA, Moore GA and Moldeus P (1994) Effect of mitochondrial
protein concentration on the efficiency of outer mitochondrial membrane removal by
the cholesterol-selective detergent digitonin. Biochim Biophy Acta 1190:304-308

Bozidis P, Williamson CD and Colberg-Poley M (2008) Mitochondrial and Secretory
Human Cytomegalovirus UL37 Proteins Traffic into Mitochondrion-Associated
Membranes of Human Cells. J Virol 82:2715-2726.

Bozzola JJ and Russell LD (1992) Electron microscopy. Jones and Bartlett
Publishers, Boston, MA.

Brailoiu E and Miyamoto MD (2000) Inositol trisphosphate and cyclic adenosine
diphosphate-ribose increase quantal transmitter release at frog motor nerve terminals:
possible involvement of smooth endoplasmic reticulum. Neuroscience 95:927–931.

Brandt JT, Martin AP, Lucas FV and Vorbeck ML (1974) The structure of rat liver
mitochondria: a reevaluation. Biochem Biophys Res Commun 59:1097-1103

Brdiczka D (1991) Contact sites between mitochondrial envelope membranes
Structure and function in energy-transfer and protein-transfer. Biochim Biophys Acta
1071:291-312.

Chapter 6 References
230
Brown MR, Sullivan PG, Dorenbos KA, Modafferi EA, Geddes JW and Steward O

(2004) Nitrogen disruption of synaptoneurosomes: an alternative method to isolate
brain mitochondria. J Neurosci Methods 137:299–303.

Bruzzone S, Guida L, Franco L, Zocchi E, Corte G and De Flora (1998) Dimeric and
tetrameric forms of catalytically active transmembrane CD38 in transfected HeLa
cells. FEBS Letters 433:275-278.

Bruzzone S, Guida L, Zocchi E, Franco L and De Flora A (2001) Connexin 43 hemi
channels mediate Ca
2+
-regulated transmembrane NAD
+
fluxes in intacT-cells.FASEB
J 15:10-12.

Bruzzone S, Verderio C, Schenk U, Fedele E, Zocchi E, Matteoli M and De Flora A.
(2004) Glutamate-mediated overexpression of CD38 in astrocytes cultured with
neurones. J Neurochem 89:264–272.

Burgess GM, Mckinney JS, Fabiato A, Leslie BA and Putney Jr JW (1983) Calcium
pools in saponin-permeabilized guinea pig hepatocytes. J Biol Chem 258:15336-
15345.
Camica O and Corazzi L (1997) Phosphatidylserine translocation into brain
mitochondria: Involvement of a fusogenic protein associated with mitochondrial
membranes. Mol Cell Biochem 175:71-80.

Cancela JM, Churchill GC and Galione A (1999) Coordination of agonist-induced
Ca
2+
-signalling patterns by NAADP in pancreatic acinar cells. Nature 398:74-6.

Cancela JM, Gerasimenko OV, Gerasimenko JV, Tepikin AV and Petersen OH
(2000) Two different but converging messenger pathways to intracellular Ca
2+

release: the roles of nicotinic acid adenine dinucleotide phosphate, cyclic ADP-ribose
and inositol trisphosphate. EMBO J 19:2549–2557.

Cancela JM, Van Coppenolle F, Galione A, Tepikin AV and Petersen OH (2002)
Transformation of local Ca
2+
spikes to global Ca
2+
transients: the combinatorial roles
of multiple Ca
2+
releasing messengers. EMBO J 21:909–919.

Carafoli E (1987) Intracellular calcium homeostasis. Annu Rev Biochem 56:395-433.

Carpenter JE, Hutchinson JA, Jackson W and Grose C. (2008) Egress of light
particles among filopodia on the surface of varicella-zoster virus infected cells. JVirol
82:2821-2835.

Cassel D & Pfeuffer T (1978) Mechanism of cholera toxin action: covalent
modification of the guanyl nucleotide-binding protein of the adenylate cyclase
system. Proc Natl Aca. Sci USA 75:2669-2673.

Ceni C, Pochon N, Brun V, Muller-Steffner H, Andrieux A, Grunwald D, Schuber F,
DeWaard M, Lund F, Villaz M and Moutin M.J (2003) CD38-dependent ADP-ribosyl

cyclase activity in developing and adult mouse brain. Biochem J 370:175-183.

Chapter 6 References
231
Ceni C, Muller-steffner H, Lund F, Pochon N, Schweitzer, De waard M, Schubber F,
Villaz M and Jo moutin M. (2003b) Evidence for an intracellular ADP-ribosyl
cyclase/NAD
+
glycohydrolase in brain from CD38-deficient mice. J Biol Chem
278:40670-40678.

Ceni C, Pochon N, Villaz M, Muller-steffner H, Schuber F, Baratier J, De waard M,
Ronjat M and Jo moutin M. (2006) The CD38-independent ADP-ribosyl cyclase from
mouse brain synaptosomes: a comparative study of neonate and adult brain. Biochem
J 395:417-426.

Chalmers, S., and Nicholls, D. G. (2003) The Relationship between Free and Total
Calcium Concentrations in the Matrix of Liver and Brain Mitochondria J. Biol. Chem.
278: 19062–19070.

Chandra NC, Spiro MJ and Spiro RG (1998) Identification of a glycoprotein from rat
liver mitochondrial inner membrane and demonstration of its origin in the
endoplasmic reticulum. J Biol Chem 273:19715–19721.

Chen J, Chen YG, Reifsnyder PC, Schott WH, Lee CH, Osborne M, Scheuplein F,
Haag F, Koch-Nolte F, Serreze DV, and Leiter EH (2006a) Targeted disruption of
CD38 accelerates autoimmune diabetes in NOD/Lt mice by enhancing autoimmunity
in an ADP- ribosyltransferase 2-dependent fashion. J Immunol 176: 4590–4599, 2006.

Chen YG, Chen J, Osborne MA, Chapman HD, Besra GS, Porcelli SA, Leiter EH,

Wilson SB, and Serreze DV (2006b) CD38 is required for the peripheral survival of
immunotolerogenic CD4-invariant NK T cells in nonobese diabetic mice. J Immunol
177:2939–2947.

Chidambaram N and Chang CF (1998) Functional role of glycosylation on the
recombinant CD38/ADP-ribosyl cyclase in CHO cells. Int J Biochem Cell Biol
30:1011-1018.

Chini EN and Dousa TP (1996) Nicotinate-adenine dinucleotide phosphate-induced
Ca
2+
-release does not behave as a Ca
2+
-induced Ca
2+
-release system. Biochem J
316:709-711.

Chini EN. (2009) CD38 as a Regulator of Cellular NAD: A Novel Potential
Pharmacological Target for Metabolic Conditions. Current Pharmaceutical Design
15:57-63

Churchill GC and Galione A (2001) NAADP induces Ca
2+
oscillations via a two-pool
mechanism by priming IP3- and cADPR-sensitive Ca
2+
stores. EMBO J 20:2666-
2671.

Churchill GC, Okada Y, Thomas JM, Genazzani AA, Patel S and Galione A (2002)
NAADP mobilizes Ca
2+
from reserve granules, lysosome-related organelles, in sea
urchin eggs. Cell 111:703-8.

Churchill GC, O'Neill JS, Masgrau R, Patel S, Thomas JM, Genazzani AA, Galione
A (2003) Sperm deliver a new second messenger: NAADP. Curr Biol 13:125-8.
Chapter 6 References
232

Cho YS, Han

MK, Choi YB, Yun

Y, Shin

J and Kim UH (2000) Direct Interaction of
the CD38 Cytoplasmic Tail and the Lck SH2 Domain: CD38 transduces T cell
activation signals through associated Lck. J Biol Chem 275:1685-1690.

Clancy R, Leszczynska J, Amin A, Levartovsky D & Abramson SB (1995) Nitric
oxide stimulates ADP ribosylation of actin in association with the inhibition of actin
polymerization in human neutrophils. J Leukoc Biol 58:196-202
.

Clapper DL, Walseth TF, Dargie PJ and Lee HC (1987) Pyridine nucleotide
metabolites stimulate calcium release from sea urchin egg microsomes desensitized to
inositol trisphosphate. J Biol Chem 262:9561-9568.

Collier RJ (1975) Diphtheria toxin: mode of action and structure. Bacteriol Rev
39:54-85.

Collins TJ, Berridge MJ, Lipp P and Bootman MD (2002) Mitochondria are
morphologically and functionally heterogeneous within cells. EMBO J 21:1616-1627.

Conley ME (1992) Molecular approaches to analysis of X-linked immunodeficiencies.
Annu Rev Immunol 10:215-238.

Cossarizza A, Ceccarelli D, Masini A (1996) Functional heterogeneity of an isolated
mitochondrial population revealed by cytofluorometric analysis at the single
organelle level. Exp Cell Res 222: 84–94.

Crompton M, Ellinger H and Costi A (1988) Inhibition by cyclosporin A of a Ca
2+
-
dependent pore in heart mitochondria activated by inorganic phosphate and oxidative
stress. Biochem J 255:357-360.

Cutrona G, Ulivi M, Fais F, Roncella S and Ferrarini M (1995) Transfection of the c-
myc oncogene into normal Epstein-Barr virus-harboring B cells results in new
phenotypic and functional features resembling those of Burkitt lymphoma cells and
normal centroblasts. J Exp Med 181:699-711.

D’Arena G, Musto P, Cascavilla N, Dell’Olio M, Di Renzo N, Perla G, Savino L and
Carotenuto M (2001) CD38 expression correlates with adverse biological features and
predicts poor clinical outcome in B-cell chronic lymphocytic leukemia. Leuk
Lymphoma 42:109–114.

D’Arena G, Nunziata G, Coppola G, Vigliotti ML, Tartarone A, Carpinelli N, Matera

R, Bisogno RC, Pistolese G and Di Renzo N (2002) CD38 expression does not
change in B-cell chronic lymphocytic leukemia. Blood 100: 3052–3053.

Davis LC, Morgan AJ, Ruas M, Woing JL, Graeff RM, Poustka AJ, Lee HC, Wessel
GM and Parrington J (2008) Ca
2+
signalling occurs via second messenger release
from intraorganelle synthesis sites. Current Biology 18:1616-1618.

Deaglio S, Dianzani U, Horenstein AL, Fernandez JE, van Kooten C, Bragardo
M, Funaro A, Garbarino G, Di Virgilio F, Banchereau J, Malavasi F (1996)


Chapter 6 References
233
Human CD38 ligand. A 120-KDA protein predominantly expressed on endothelial
cells. J Immunol 156: 727–734.

Deaglio S, Morra M, Mallone R, Ausiello CM, Prager E, Garbarino G, Dianzani U,
Stockinger H and Malavasi F (1998) Human CD38 (ADP-ribosyl cyclase) is a
counter-receptor of CD31, an Ig superfamily member. J Immunol 160:395-402.

Deaglio S, Mallone R, Baj G, Arnulfo A, Surico N, Dianzani U, Mehta K and
Malavasi F (2000) CD38/CD31, a receptor/ligand system ruling adhesion and
signaling in human leukocytes. Chem Immunol 75:99–120.

Deaglio S, Mehta K, Malavasi F (2001) Human CD38: A (r) evolutionary story of
enzymes and receptors. Leuk Res 25:1-12.

Deaglio S, Capobianco A, Bergui L, Durig J, Morabito F, Duhrsen U and Malavasi F

(2003) CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells.
Blood 102: 2146–2155.

Deaglio S, Vaisitti T, Bergui L, Bonello L, Horenstein AL, Tamagnone L, Boumsell
L and Malavasi F (2005) CD38 and CD100 lead a network of surface receptors
relaying positive signals for B-CLL growth and survival. Blood 105: 3042–3050.

De Harven E, Christensen H, Poppema S and Scott JG (1993) Immunogold labelling
of leukemic hairy cells with the B-ly7 monoclonal antibody: an SEM and TEM study.
Microsc Res Tech 28:356-367.

de Harven E, Leung R and Christensen H (1984) Novel approach for scanning
electron microscopy of colloidal gold-labeled cell surfaces JCB, 99:53-57.

De Flora A, Guida L, Franco L, Zocchi E, Pestarino M, Usai C, Marchetti C, Fedele
E, Fontana G and Raiteri M (1996) Ectocellular in vitro and in vivo metabolism of
cADP-ribose in cerebellum. Biochem J. 320:665–671.

De Flora A, Guida L, Franco L and Zocchi E (1997) The CD38/cyclic ADP-ribose
System: a Topological Paradox. Int J Biochem cell biol. 29:ll49-1166.

De Flora A, Franco L, Guida L, Bruzzone S, and Zocchi E (1998) Ectocellular CD38-
catalyzed synthesis and intracellular Ca
2+
-mobilizing activity of cyclic ADP-ribose.
Cell biochem biophys 28:45-62.

De Harven, Leong R and Christensen (1984) A novel approach for scanning electron
microscopy of colloidal gold-labeled cell surfaces. J Cell Biol 99:53-57.

da Silva CP, Schweitzer K, Heyer P, Malavasi F, Mayr GW and Guse AH (1998)
Ectocellular CD38-catalyzed synthesis and intracellular Ca
2+
-signaling activity of
cyclic ADP-ribose in T-lymphocytes are not functionally relatd. FEBS Lett. 439:291-
296.

Del Poeta G, Maurillo L, Venditti A, Buccisano F, Epiceno AM, Capelli G,
Tamburini A, Suppo G, Battaglia A, Del Principe MI, Del Moro B, Masi M and
Chapter 6 References
234
Amadori S (2001) Clinical significance of CD38 expression in chronic lymphocytic
leukemia. Blood 98:2633–2639.

Deshpande DA, White TA, Dogan S, Walseth TF, Panettieri RA and Kannan MS
(2005) CD38/cyclic ADP-ribose signaling: role in the regulation of calcium
homeostasis in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 288:
L773–L788.

Di Virgilio F, Mutini C, Chiozzi P, Falzoni S, Dal Susino M, Sanz J M and Ferrari D
(1996) A purinergic hypothesis for immunomodulation. Ital J Biochern 45:195-203.

Dianzani U, Funaro A, DiFranco D, Garbarino G, Bragardo M, Redoglia V,
Buonfiglio D, De Monte LB, Pileri A and Malavasi F (1994) Interaction between
endothelium and CD4
+
CD45RA
+
lymphocytes: Role of the human CD38 molecule. J
Immunol 153:952-959.

Diekert K, Kispal G, Guiard B & Lill R (1999) A novel targeting signal directing
proteins into the mitochondrial intermembrane space. Proc Natl Acad Sci U.S.A
96:11752-11757.

Dogan S, White TA, Deshpande DA, Murtaugh MP, Walseth TF and Kannan MS
(2002) Estrogen increases CD38 gene expression and leads to differential regulation
of adenosine diphosphate (ADP)-ribosyl cyclase and cyclic ADP-ribose hydrolase
activities in rat myometrium. Biol Reprod 66:596-602.

Dogan S, Deshpande DA, Kannan MS and Walseth TF (2004) Changes in CD38
expression and ADP-ribosyl cyclase activity in rat myometrium during pregnancy:
influence of sex steroid hormones. Biol Reprod 71:97-103.

Dogan S, Deshpande DA, White TA, Walseth TF, Kannan MS (2006) Regulation of
CD 38 expression and function by steroid hormones in myometrium. Mol Cell
Endocrinol 246:101-106.

Domingo-Domenech E, Domingo-Claros A, Gonzalez-Barca E, Beneitez D, Alonso
E, Romagosa V, De Sanjos S, Petit J, Granena A and Fernandez de Sevilla A (2002)
CD38 expression in Bchronic lymphocytic leukemia: association with clinical
presentation and outcome in 155 patients. Haematologica 87:1021–1027.

Donzeau M, Kaldi K, Adm A, Paschen S, Wanner G, Guiard B, Bauer MF, Neupert
W and Brunner M (2000) Tim23 links the inner and outer mitochondrial membranes.
Cell 101:410-412

Drach J, McQueen T, Engel H, Andreeff M, Robertson KA, Collins SJ, Malavasi F
and Mehta K (1994) Retinoic acid-induced expression of CD38 antigen in myeloid
cells is mediated through retinoic acid receptor-alpha. Cancer Res 54:1746-1752.

Durig J, Naschar M, Schmucker U, Renzing-Kohler K, Holter T, Huttmann A and
Duhrsen U (2002) CD38 expression is an important prognostic marker in chronic
lymphocytic leukaemia. Leukemia 16:30–35.

Chapter 6 References
235
Ellis JH, Barber KA, Tutt A, Hale C, Lewis AP, Glennie MJ, Stevenson GT and
Crowe JS (1995) Engineered anti-CD38 monoclonal antibodies for immunotherapy of
multiple myeloma. J Immunol 155:925–937.

Fagian MM, Pereira-da-Silva L, Martins IS and Vercesi AE (1990) Membrane
protein thiol cross-linking associated with the permeabilization of the inner
mitochondrial membrane by Ca2+ plus prooxidants. J Biol Chem 265:19955-19960.

Fedele G, Frasca L, Palazzo R, Ferrero E, Malavasi F and Ausiello CM (2004) CD38
is expressed on human mature monocyte-derived dendritic cells and is functionally
involved in CD83 expression and IL-12 induction. Eur J Immunol 34:1342-1350.

Ferrero E and Malavasi F (1999) The metamorphosis of a molecule: from soluble
enzyme to the leukocyte receptor CD38. J Leukoc Biol 65:151-161.

Fernandez JE, Deaglio S, Donati D, Beusan IS, Corno F, Aranega A, Forni M, Falini
B and Malavasi F (1998) Analysis of the distribution of human CD38 and of its
ligand CD31 in normal tissues. J Biol Regul Homeost Agents 12:81-91.

Fernandez-Vizarra E, Lopez-Perez MJ and Enriquez JA (2002) Isolation of
biogenetically competent mitochondria from mammalian tissues and cultured cells.
Method 26:292-297

Filippin L, Magalhaes PJ, Di Benedetto G, Colella M and Pozzan T (2003) Stable
interactions between mitochondria and endoplasmic reticulum allow rapid
accumulation of calcium in a subpopulation of mitochondria. J Biol Chem
278:39224–39234.

Flavell DJ, Cooper S, Morland B, French R and Flavell SU (1992) Effectiveness of
combinations of bispecific antibodies for delivering saporin to human acute T-cell
lymphoblastic leukaemia cell lines via CD7 and CD38 as cellular target molecules. Br
J Cancer 65:545-551.

Flavell DJ, Boehm DA, Emery L, Noss A, Ramsay A, and Flavell SU (1995) Therapy
of human B-cell lymphoma bearing SCID mice is more effective with anti-CD19- and
anti-CD38-saporin immunotoxins used in combination than with either immunotoxin
used alone. Int J Cancer 62:337-344.

Fliegert R, Gasser A and Guse AH (2007) Regulation of calcium signalling by
adenine-based second messengers. Biochem Soc Trans 35: 109–114.

Franco L, Zocchi E, Calder L, Guida L, Benatti U and De Flora A (1994) Self-
Aggregation of the Transmembrane Glycoprotein CD38 Purified from Human
Erythrocytes Biochem. Biophys. Res. Commun. 202:1710-1715.

Franco L, Guida L, Bruzzone S, Zocchi E, Usai C, De Flora A (1998) The
transmembrane glycoprotein CD38 is a catalytically active transporter responsible for
generation and influx of the second messenger cyclic ADP-ribose across membranes.
FASEB J 12:1507–1520.

Chapter 6 References
236
Franco L, Zocchi E, Usai C, Guida L, Bruzzone S, Costa A and De Flora A (2001)

Paracrine Roles of NAD
+
and Cyclic ADP-ribose in Increasing Intracellular Calcium
and Enhancing Cell Proliferation of 3T3 Fibroblasts J. Biol. Chem. 276:21642–21648

Frasca L, Fedele G, Deaglio S, Capuano C, Palazzo R, Vaisitti T, Malavasi F and
Ausiello CM (2006) CD38 orchestrates migration, survival, and Th1 immune
response of human mature dendritic cells. Blood 107: 2392–2399, 2006.

French RR, Penney CA, Browning AC, Stirpe F, George AJ and Glennie MJ (1995)
Delivery of the ribosome-inactivating protein, gelonin, to lymphoma cells via CD22
and CD38 using bispecific antibodies. Br J Cancer 71:986-994.

Frey TG and Mannella CA (2000) The internal structure of mitochondria. Trends
Biochem Sci 25: 319–324.

Fukushi Y, Kato I, Takasawa S, Sasaki T, Ong BH, Sato M, Ohsaga A, Sato K,
Shirato K, Okamoto H and Maruyama Y (2001) Identification of cyclic ADP-ribose-
dependent mechanisms in pancreatic muscarinic Ca
2+
signaling using CD38 knockout
mice. J Biol Chem 276: 649–655.

Funaro A, Spagnoli GC, Ausiello CM, Alessio M, Roggero S, Delia D, Zaccolo M
and Malavasi F (1990) Involvement of the multilineage CD38 molecule in a unique
pathway of cell activation and proliferation. J Immunol 145:2390-2396.

Funaro A, De Monte LB, Dianzani U, Forni M and Malavasi F (1993) Human CD38
is associated to distinct molecules which mediate transmembrane signaling in
different lineages. Eur J Immunol 23:2407–2411.

Funaro A, Morra M, Calosso L, Zini MG, Ausiello CM and Malavasi F (1997) Role
of the human CD38 molecule in B cell activation and proliferation. Tissue Antigens
49:7-15.

Fujita T, Zawawi KH, Kurihara H and Van Dyke TE (2005) CD38 cleavage in fMLP-
and IL-8-induced chemotaxis is dependent on p38 MAP kinase but independent of
p44/42 MAP kinase. Cell Signal 17:167–175.

Frei B and Richter C (1986) N-methyl-4-phenylpyridine (MMP
+
) together with 6-
hydroxydopamine or dopamine stimulates Ca2+ release from mitochondria. FEBS
Lett 198:99-102.

Gagne JP, Hendzel MJ, Droit A and Poirier GG (2006) The expanding role of
poly(ADP-ribose) metabolism: current challenges and new perspectives. Curr Opin
Cell Biol. 18:145-51.

Galione A, Lee HC, and Busa WB (1991) Ca
2+
induced Ca
2+
release in sea urchin egg
homogenates: modulation by cyclic ADP-ribose. Science 253:1143-1146.

Garnier JL, Stevenson G, Blanc-Brunat N, Touraine JL, Milpied N, Leblond V, Blay
JY (2002) Treatment of post-transplant lymphomas with anti-B-cell monoclonal
antibodies. Recent Results Cancer Res 159:113–122.
Chapter 6 References

237

Gartner F, Voos W, Querol A, Miller BR, Craig EA, Cumsky MG & Pfanner N (1995)
Mitochondrial Import of Subunit Va of Cytochrome c Oxidase Characterized with
Yeast Mutants. J Biol Chem 270: 3788-3795.

Gasser A, Glassmeier G, Fliegert R, Langhorst MF, Meinke S, Hein D, Kruger S,
Weber K, Heiner I, Oppenheimer N, Schwarz JR and Guse AH (2006) Activation of
T cell calcium influx by the second messenger ADP-ribose. J Biol Chem 281: 2489–
2496.

Gelman L, Deterre P, Gouy H, Boumsell L, Debre P, Bismuth G (1993) The
lymphocyte surface antigen CD38 acts as a nicotinamide adenine dinucleotide
glycohydrolase in human T lymphocytes. Eur J Immunol 23: 3361–3364.

Genazzani AA, Bak J, and Galione A (1996) Inhibition of cADPR-Hydrolase by
ADP-ribose potentiates cADPR synthesis from beta-NAD
+
. Biochem Biophys Res
Commun 223:502-507.

Gerasimenko OV, Gerasimenko JV, Tepikin AV and Petersen OH (1995) ATP-
dependent accumulation and inositol trisphosphate- or cyclic ADP-ribose-mediated
release of Ca
2+
from the nuclear envelope. Cell 80:439-44.

Gerencser AA, Adam-Vizi V (2005) Mitochondrial Ca
2+
dynamics reveals

limited intramitochondrial Ca
2+
diffusion. Biophys J 88: 698–714.

Graf M, Frei B, Winterhalter KH and Richter C (1985) Divicine induces calcium
release from rat liver mitochondria. Biochem Biophys Res Commun 129:18-25.

Graeff RM, Walseth TF, Fryxell K, Branton WD and Lee HC (1994) Enzymatic
synthesis and characterizations of cyclic GDP-ribose. A procedure for distinguishing
enzymes with ADP-ribosyl cyclase activity. J Biol Chem 269:30260-30267.

Graeff RM, Walseth TF, Hill HK and Lee HC (1996) Fluorescent analogs of cyclic
ADP-ribose: synthesis, spectral characterization, and use. Biochemistry 35:379-386.

Graeff RM, Walseth TF and Lee HC (1997) Radioimmunoassay for measuring
endogenous levels of cyclic ADP-ribose in tissues. Methods Enzymol 280:230-241.

Graeff R, Liu Q, Kriksunov IA, Hao Q and Lee HC (2006) Acidic residues at the
active sites of CD38 and ADP-ribosyl cyclase determine NAADP synthesis and
hydrolysis activities. J Biol Chem 281:28951-28957.

Green S and Bodansky O (1964) Some properties of the enzyme nicotinamide
adenine dinucleotide glycohydrolase from mouse ehrlich ascites cells. J Biol Chem
239:2613-2617.

Greenawalt JW (1974) The isolation of outer and inner mitochondrial membranes.
Methods Enzymol. 31:310–323.

Chapter 6 References
238

Grimaldi JC, Balasubramanian S, Kabra NH, Shanafelt A, Bazan JF, Zurawski G and
Howard MC (1995) CD38-mediated ribosylation of proteins. J Immunol 155:811-817.
Griparic L, van der Wel NN, Orozco IJ, Peters PJ, and van der Bliek AM (2004)
Loss of the intermembrane space protein Mgm1/OPA 1 induces swelling and
localized constrictions along the lengths of mitochondria. J Biol Chem 279, 18792-
18798
Goodrich SP, Muller-Steffner H, Osman A, Moutin MJ, Kusser K, Roberts A,
Woodland DL, Randall TD, Kellenberger E, LoVerde PT, Schuber F and Lund FE
(2005) Production of calcium-mobilizing metabolites by a novel member of the ADP-
ribosyl cyclase family expressed in Schistosoma mansoni. Biochemistry. 44:11082–
97.

Gonzalez-Garcia M, Perez-Ballestero R, Ding L, Duan L, Boise LH, Thompson CB,
and Nunez D (1994) Bcl-xL is the major Bcl-x mRNA form expressed during murine
development and its product localizes to mitochondria. Development 120:3033–3042.

Gordon JL (1986) Extracellular ATP: effects, sources and fate. Biochem J 233:309-
319.

Guida L, Franco L, Zocchi E, and De Flora A (1995) Structural role of disulfide
bridges in the cyclic ADP-ribose related bifunctional ectoenzyme CD38. FEBS Lett
368:481-484.

Guida L, Bruzzone S, Sturla L, Franco L, Zocchi E and De Flora A (2002)
Equilibrative and concentrative nucleoside transporters mediate influx of extracellular
cyclic ADP-ribose into 3T3 murine fibroblasts. J Biol Chem 277:47097–47105.

Gunter, T. E., Gunter, K. K., Sheu, S. S., and Gavin, C. E. (1994) Mitochondrial
calcium transport: physiological and pathological relevance. Am J P Am. J. Physiol.
267:C313–C339

Gurubhagavatula I, Amrani Y and Pratico D (1998) Engagement of human PECAM-1
(CD31) on human endothelial cells increases intracellular calcium ion concentration
and stimulates prostacyclin release. J Clin Invest 101:212–222.

Guse AH (1999) Cyclic ADP-ribose: A novel Ca
2+
mobilizing second messenger.
Cell Signal 11:309-316.

Guse AH (2005) Second messenger function and the structure–activity relationship of
cyclic adenosine diphosphoribose (cADPR). FEBS J 272:4590-4597.

Hada H, Honda C, and Tanemura H (1977) Spectroscopic study on the J-aggregate of
cyanine dyes.1. Spectral changes of UV bands concerned with J-agregate formation.
photogr Sci Eng 21:83-91.

Hamblin TJ, Orchard JA, Gardiner A, Oscier DG, Davis Z and Stevenson FK (2000)
Immunoglobulin V genes and CD38 expression in CLL. Blood 95:2455–2457.

Chapter 6 References
239
Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK, Oscier
DG (2002) CD38 expression and immunoglobulin variable region mutations are
independent prognostic variables in chronic lymphocytic leukemia, but CD38
expression may vary during the course of the disease. Blood 99:1023–1029.

Han MK, Cho YS, Kim YS, Yim CY and Kim UH (2000) Interaction of two classes
of ADP-ribose transfer reactions in immune signaling. J Biol Chem 275:20799-
20805.

Harada N, Santos-Argumedo L, Chang R, Grimaldi JC, Lund FE, Brannan CI,
Copeland NG, Jenkins NA, Heath AW, Parkhouse RM and Howard M (1993)
Expression cloning of a cDNA encoding a novel murine B cell activation marker,
homology to human CD38. J Immunol 151:3111-3118.

Hara-Yokoyama M, Kukimoto I, Nishina H, Kontani K, Hirabayashi Y, Irie F, Sugiya
H, Furuyama S and Katada T (1996) Inhibition of NAD
+
glycohydrolase and ADP-
ribosyl cyclase activities of leukocyte cell surface antigen CD38 by gangliosides. J
Biol Chem 271:12951–12955.

Hart GW (1997) Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins.
Annu Rev Biochem 66:315–335.

Hasmann M and Schemainda I (2003) FK866, a Highly Specific Noncompetitive
Inhibitor of Nicotinamide Phosphoribosyltransferase, Represents a Novel Mechanism
for Induction of Tumor Cell Apoptosis. Cancer Res 63:7436-7442.

Heisea K, Puntarulob S, Portnera H O, Abele D (2003) Production of reactive oxygen
species by isolated mitochondria of the Antarctic bivalve Laternula elliptica (King
and Broderip) under heat stress. Comp Biochem Physiol C Toxicol Pharmacol
134:79-90.

Hellmich MR and Strumwasser F (1991) Purification and characterization of a
molluscan egg-specific NADase, a second-messenger enzyme. Cell Regul 2:193-202.

Higashida H, Salmina AB, Olovyannikova RY, Hashii M, Yokoyama S, Koizumi K,
Jin D, Liu HX, Lopatina O, Amina S, Islam MS, Huang JJ and Noda M (2007) Cyclic

ADP-ribose as a universal calcium signal molecule in the nervous system. Neurochem
Int 51:192–199.

Higashida H, Bowden SE, Yokoyama S, Salmina A, Hashii M, Hoshi N, Zhang JS,
Knijnik R, Noda M, Zhong ZG, Jin D, Higashida K, Takeda H, Akita T, Kuba K,
Yamagishi S, Shimizu N, Takasawa S, Okamoto H, and Robbins J (2007)
Overexpression of human CD38/ADP-ribosyl cyclase enhances acetylcholine induced
Ca
2+
signalling in rodent NG108–15 neuroblastoma cells. Neurosci Res 57: 339–346.

Hiller MM, Finger A, Schweiger M and Wolf DH (1996) ER degradation of a
misfolded luminal protein by the cytosolic ubiquitin/proteasome pathway. Science
273: 1725-1728.

Chapter 6 References
240
Hilz H, Koch R, Fanick W, Klapproth K and Adamietz P (1984) Proc Natl Acad Sci
USA 81:3929-3933.

Hobot JA, Carlemalm E, Villiger W, and Kellenberger E (1984). Periplasmic gel:
new concept resulting from the reinvestigation of bacterial cell envelope
ultrastructure by new methods. J Bacteriol 160: 143-152.

Hoffmann C, Tiemann M, Schrader C, Janssen D, Wolf E, Vierbuchen M,
Parwaresch R, Ernestus K, Plettenberg A, Stoehr A, Fatkenheuer G, Wyen C, Oette
M and Horst HA (2005) AIDS related B-cell lymphoma (ARL): correlation of
prognosis with differentiation profiles assessed by immunophenotyping. Blood
106:1762–1769.

Horikoshi H, Kinomoto M, Sasao F, Mukai T, Luftig RB and Ikuta K (2001)
Differential susceptibility of resting CD4
+
T lymphocytes to a T-tropic and a
macrophage (M)-tropic human immunodeficiency virus type 1 is associated with their
surface expression of CD38 molecules. Virus Res 73: 1–16.

Hoshino S, Kukimoto I, Kontani K, Inoue S, Kanda Y, Malavasi F and Katada T
(1997) Mapping of the catalytic and epitopic sites of human CD38/NAD+
glycohydrolase to a functional domain in the carboxyl terminus. J Immunol 158:741-
747.

Hotta T, Asai K, Fujita K, Kato T and Higashida H (2000) Membrane-bound form of
ADP-ribosyl cyclase in rat cortical astrocytes in culture. J Neurochem 74:669–675.

Howard M, Grimaldi JC, Bazan JF, Lund FE, Santos-Argumedo L, Parkhouse RM,
Walseth TF and Lee HC (1993) Formation and hydrolysis of cyclic ADP-ribose
catalyzed by lymphocyte antigen CD38. Science 262:1056-1059.

Hsu SM, Raine L and Fanger H (1981) Use of avidin-biotin-peroxidase complex
(ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled
antibody (PAP) procedures. J Histochem Cytochem 29:577–580.

Ibrahim S, Keating M, Do KA, O’Brien S, Huh YO, Jilani I, Lerner S, Kantarjian HM
and Albitar M (2001) CD38 expression as an important prognostic factor in B-cell
chronic lymphocytic leukemia. Blood 98:181–186, 2001.

Ichas F, Jouaville LS, Mazat JP. Mitochondria are excitable organelles capable of
generating and conveying electrical and calcium signals. Cell 89: 1145–1153, 1997.

Ikehata F, Satoh J, Nata K, Tohgo A, Nakazawa T, Kato I, Kobayashi S, Akiyama T,
Takasawa S, Toyota T and Okamoto H (1998) Autoantibodies against CD38 (ADP-
ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin
secretion in noninsulin- dependent diabetes patients. J Clin Invest 102:395-401.

Inoue S, Kontani K, Tsujimoto N, Kanda Y, Hosoda N, Hoshino S, Hazeki O and
Katada T (1997) Protein-tyrosine phosphorylation by IgG1 subclass CD38
monoclonal antibodies is mediated through stimulation of the FcgammaII receptors in
human myeloid cell lines. J Immunol 159:5226-5232.