Equilibrative and Concentrative Nucleoside Transporters Mediate Influx of Extracellular Cyclic ADP-Ribose into 3T3 Murine Fibroblasts

Guida, Lucrezia; Bruzzone, Santina; Sturla, Laura; Franco, Luisa; Zocchi, Elena; Flora, Antonio De

doi:10.1074/jbc.m207793200

Cited by 68 publications

(81 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is difficult to envision how cADPR and NAADP can function inside the cell if they are generated by ectoenzymes. Several studies suggest that cADPR and NAADP are directly transported by CD38 or more likely by nucleotide transporters into the cytosol [10][11][12][13][14]. So far, in many cell types, responding to extracellular NAD + with an increase in [Ca 2+ ] i , conversion of NAD + to the Ca 2+ mobilizer cADPR [14][15][16][17][18] has been implicated as the principal mechanism leading to the rise in [Ca 2+ ] i .…”

Section: Introductionmentioning

confidence: 99%

Involvement of P2X receptors in the NAD+-induced rise in [Ca2+]i in human monocytes

Grahnert

Klein

Hauschildt

2009

Purinergic Signalling

View full text Add to dashboard Cite

In the present study, we show that the extracellular addition of nicotinamide adenine dinucleotide (NAD + ) induces a transient rise in [Ca 2+ ] i in human monocytes caused by an influx of extracellular calcium. The NAD + -induced Ca 2+ response was prevented by adenosine triphosphate (ATP), suggesting the involvement of ATP receptors. Of the two subtypes of ATP receptors (P2X and P2Y), the P2X receptors were considered the most likely candidates. By the use of subtype preferential agonists and antagonists, we identified P2X 1 , P2X 4 , and P2X 7 receptors being engaged in the NAD + -induced rise in [Ca 2+ ] i . Among the P2X receptor subtypes, the P2X 7 receptor is unique in facilitating the induction of nonselective pores that allow entry of ethidium upon stimulation with ATP. In monocytes, opening of P2X 7 receptor-dependent pores strongly depends on specific ionic conditions. Measuring pore formation in response to NAD + , we found that NAD + unlike ATP lacks the ability to induce this pore-forming response. Whereas as little as 100 μM ATP was sufficient to activate the nonselective pore, NAD + at concentrations up to 2 mM had no effect. Taken together, these data indicate that despite similarities in the action of extracellular NAD + and ATP there are nucleotide-specific variations. So far, common and distinct features of the two nucleotides are only beginning to be understood.

show abstract

Section: Introductionmentioning

confidence: 99%

Involvement of P2X receptors in the NAD+-induced rise in [Ca2+]i in human monocytes

Grahnert

Klein

Hauschildt

2009

Purinergic Signalling

View full text Add to dashboard Cite

show abstract

“…The precursor NAD + is released from the cytoplasm into the medium through Cx43 hemichannels, as indicated by: (i) dependence on level of Cx43 expression in transfected or antisensetreated cells; (ii) sensitivity to gap-junction blockers; and (iii) influx into and efflux from liposomes incorporating isolated Cx43. cADPR is also synthesized in intracellular vesicles transporting CD38 to or from the surface; NAD + enters the vesicles through Cx43 hemichannels and cADPR moves to the cytoplasm by action of the same nucleotide transporters that operate in the surface membrane [33,55]. This pathway of synthesis would prevent loss of NAD + and cADPR by diffusion away from an ectoenzyme, but also prevent paracrine action.…”

Section: An Extracellular Signal Released Through Hemichannelsmentioning

confidence: 99%

“…Surprisingly, it is synthesized by the ectoenzyme CD38, an integral membrane protein with an extracellular active site that cyclizes NAD + to form cADPR ( Figure 2). cADPR, which does not permeate Cx43 hemichannels [31,33], reaches its site of action on ryanodine receptors by both active and passive transport across the surface membrane [55]. It can also have a paracrine action, which might be why an ectoenzyme is used.…”

Section: An Extracellular Signal Released Through Hemichannelsmentioning

confidence: 99%

New roles for astrocytes: Gap junction hemichannels have something to communicate

Bennett

Contreras

Bukauskas

et al. 2003

Trends in Neurosciences

376

279

View full text Add to dashboard Cite

Gap junctions are clusters of aqueous channels that connect the cytoplasm of adjoining cells. Each cell contributes a hemichannel, or connexon, to each cell-cell channel. The cell-cell channels are permeable to relatively large molecules, and it was thought that opening of hemichannels to the extracellular space would kill cells through loss of metabolites, collapse of ionic gradients and influx of Ca 2+ . Recent findings indicate that specific non-junctional hemichannels do open under both physiological and pathological conditions, and that opening is functional or deleterious depending on the situation. Most of these studies utilized cells in tissue culture that expressed a specific gap junction protein, connexin 43. Several such examples are reviewed here, with a particular focus on astrocytes.Gap junctions mediate intercellular communication by providing ultrastructural cytoplasmic continuity, and they are integral to formation of the functional syncytium of astrocytes. Each of the joined cells contributes a hemichannel or connexon to each cell-cell channel ( Figure 1; Box 1). Each hemichannel comprises a hexamer of connexins arranged around a central pore, and the cell-cell channels are gated by several stimuli, including transjunctional voltage, low pH and various pharmacological agents. Connexins are encoded by a gene family with at least 20 members in mammals [1].Gap-junction pores are nominally 1.0-1.5 nm in diameter and are permeable to molecules of 1 kDa [2]. Junctions formed from connexin 43 (Cx43), the predominant connexin in astrocytes, are permeable to Lucifer Yellow (443 Da, −2 charge) and propidium (420 Da, +2 charge). Other connexins appear to be more charge selective: Cx32 is more permeable to anions and Cx45 is more permeable to cations [2]. Single-channel conductance varies widely, from ~15 pS for Cx36 [3] and 110 pS for Cx43 [4] to ~375 pS for Cx37 [5]. The maximum size of permeant species also varies. Such diversity in selectivity and conductance are likely to account for the expansion of the connexin family. Why shouldn't hemichannels be open?Given the permeability and conductance of gap junctions, and the expectation that an open hemichannel would have twice the conductance and permeability of a cell-cell channel (in terms of ion or molecular flux, rather than selectivity), it was thought unlikely that hemichannels in the non-junctional membrane would open [6]. Direct evidence for this was provided by measurements during formation of the first channel between a newly apposed pair of cells. Each cell was held at a different potential, and then when the first channel NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript opened, increased current was seen in the cell held at a more positive potential and decreased (more negative) current was seen in the other cell, but the sum of the currents clamping the two cells remained constant [7]. Thus, there was no change in the current flowing into the extracellular space, and the hemichannels were closed before openin...

show abstract

“…To investigate this possibility, we examined whether there is any interdependence between cADPR and NAADP production by taking advantage of transporting cADPR and NAADP to LAK cells (supplemental Fig. S1) like other cells known to be transported (35)(36)(37). The addition of exogenous cADPR to LAK cells enhanced intracellular NAADP levels, whereas the addition of NAADP failed to increase intracellular cADPR levels (Fig.…”

Section: Treatment Of Lak Cells With Il-8mentioning

confidence: 99%

Generation of Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate by CD38 for Ca2+ Signaling in Interleukin-8-treated Lymphokine-activated Killer Cells

Rah

Mushtaq

Nam

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

We have previously demonstrated that cyclic ADP-ribose (cADPR) is a calcium signaling messenger in interleukin 8 (IL-8)-induced lymphokine-activated killer (LAK) cells. In this study we examined the possibility that IL-8 activates CD38 to produce another messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), in LAK cells, and we showed that IL-8 induced NAADP formation after cADPR production. These calcium signaling messengers were not produced when LAK cells prepared from CD38 knock-out mice were treated with IL-8, indicating that the synthesis of both NAADP and cADPR is catalyzed by CD38 in LAK cells. Application of cADPR to LAK cells induced NAADP production, whereas NAADP failed to increase intracellular cADPR levels, confirming that the production of cADPR precedes that of NAADP in IL-8-treated LAK cells. Moreover, NAADP increased intracellular Ca 2؉ signaling as well as cell migration, which was completely blocked by bafilomycin A1, suggesting that NAADP is generated in lysosome-related organelles after cADPR production. A type II transmembrane protein, CD38, possesses ADP-ribosyl cyclase (ADPR cyclase) 3 and cyclic ADP-ribose hydrolase (cADPR hydrolase) activity (1, 2). These two enzyme activities are involved in the conversion of ␤-nicotinamide adenine dinucleotide (␤-NAD ϩ ) first to cADPR and then to ADPR (3-5). The metabolite cADPR is known to increase intracellular Ca 2ϩ concentration, [Ca 2ϩ ] i , by releasing Ca 2ϩ from intracellular stores or by Ca 2ϩ influx through plasma membrane Ca 2ϩ channels in a variety of cells (6 -10). It was shown that CD38 can also synthesize NAADP from NADP in the presence of nicotinic acid by a base exchange reaction in vitro (11). However, it still remains unclear whether the base exchange reaction occurs physiologically as intracellular nicotinic acid concentration is less than the millimolar concentration that is required for the enzymatic synthesis of nicotinic acid adenine dinucleotide phosphate (NAADP) in vitro (12).NAADP is a potent Ca 2ϩ -releasing messenger in a variety of cell types, including mammalian cells (13-15). Although D-myo-inositol 1,4,5-trisphosphate (IP 3 ) and cADPR are firmly established as secondary Ca 2ϩ messengers, receptor-mediated formation of NAADP has been shown in a limited number of cellular systems (16 -18). It has been demonstrated that NAADP triggers Ca 2ϩ release from thapsigargin-insensitive Ca 2ϩ stores through the activation of channels distinct from those sensitive to ryanodine and IP 3 (19). In sea urchin eggs, NAADP releases Ca 2ϩ from acidic Ca 2ϩ stores, lysosome-related organelles (20). However, NAADP can also release Ca 2ϩ from the endoplasmic reticulum (21-23).Previously, we have reported that IL-8 stimulated cADPR formation by activation of CD38 via cGMP/protein kinase G and induced an increase of [Ca 2ϩ ] i and migration of LAK cells (24). In this study we investigated whether NAADP is involved in IL-8-induced Ca 2ϩ signaling and migration of LAK cells. We showed that NAADP plays a key role in IL-8-stimul...

show abstract

Equilibrative and Concentrative Nucleoside Transporters Mediate Influx of Extracellular Cyclic ADP-Ribose into 3T3 Murine Fibroblasts

Cited by 68 publications

References 57 publications

Involvement of P2X receptors in the NAD+-induced rise in [Ca2+]i in human monocytes

Involvement of P2X receptors in the NAD+-induced rise in [Ca2+]i in human monocytes

New roles for astrocytes: Gap junction hemichannels have something to communicate

Generation of Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate by CD38 for Ca2+ Signaling in Interleukin-8-treated Lymphokine-activated Killer Cells

Contact Info

Product

Resources

About