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Connexin 43 hemi channels mediate Ca²⁺-regulated transmembrane NAD⁺ fluxes in intact cells¹

SANTINA BRUZZONE^*, LUCREZIA GUIDA^*, ELENA ZOCCHI^*, LUISA FRANCO and ANTONIO DE FLORA^*2

^* Department of Experimental Medicine, Section of Biochemistry, University of Genova, 16132 Genova, Italy; and
Biocrystallography Center-CNR, University Federico II, 80134 Naples, Italy

²Correspondence: Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy. E-mail: toninodf{at}unige.it

SPECIFIC AIMS

Several mammalian cell types have been recently shown to express a NAD⁺ transport system on the plasma membrane. The fundamental and pleiotropic roles played by NAD⁺ in physiological processes (ranging from redox reactions and metabolism, signaling mechanisms, and DNA repair) prompted us to characterize the NAD⁺ transporter of NIH 3T3 fibroblasts, since this murine cell line had previously been shown to exhibit gradient-directed transmembrane fluxes of NAD⁺, both influx of externally added NAD⁺ and release of intracellular NAD⁺ into the medium.

PRINCIPAL FINDINGS

1. The NAD⁺ transporter from 3T3 cells can be reconstituted into unilamellar proteoliposomes
Total membrane proteins from 3T3 fibroblasts were reconstituted into unilamellar proteoliposomes, which were then tested for NAD⁺ influx using either ³²[P]-NAD⁺ or unlabeled dinucleotide. This process was dependent on time, protein concentration, and pH, with maximum influx being observed at pH 8.3. Influx of NAD⁺ was almost completely inhibited by NADP⁺, NADPH, NADH, nicotinamide, ADP, ATP, and FAD. GSSG and thiol reagents abolished NAD⁺ transport completely.

2. Calcium inhibits NAD⁺ transport across the plasma membrane of intact 3T3 fibroblasts
Although NAD⁺ transport in reconstituted proteoliposomes was unaffected by Ca²⁺, extracellular and intracellular Ca²⁺ were found to inhibit influx and efflux of NAD⁺ in intact 3T3 cells. Chelation of extracellular Ca²⁺ (5 mM EDTA) increased threefold NAD⁺ transport (both influx and release) over values observed in Ca²⁺-containing medium (DME) (Fig. 1a ). Increasing intracellular Ca²⁺ by means of 20 µM A23187 ionophore blocked NAD⁺ fluxes completely (Fig. 1a ). Moreover, extracellular Ca²⁺ inhibited NAD⁺ influx in a concentration-dependent fashion (Fig. 1b ).

View larger version (18K): [in this window] [in a new window]   Figure 1. Inhibition by Ca2+ of NAD+ transport in intact 3T3 fibroblasts. a) Chelation of extracellular Ca2+ (5 mM EDTA) and intracellular Ca2+ loading (20 µM A23187) affect influx (white bars, n=5) and efflux (hatched bars, n=5) of NAD+ in intact 3T3 murine fibroblasts. b) Concentration-dependence of inhibition of NAD+ transport by extracellular Ca2+ (n=5). NAD+ influx was determined by resuspending cells in a medium (Ca2+-free 150 mM NaCl in 10 mM Tris-HCl, pH 8.3) supplemented with different Ca2+ concentrations. Values are means ± sd.<

3. Gap junction blockers inhibit NAD⁺ transport across 3T3 cell membranes
All properties observed for passive NAD⁺ transport across native cell membranes and membrane protein reconstituted proteoliposomes were reminiscent of transport processes mediated by gap junction channels. These are formed by the juxtaposition of two hemi channels on the membranes of two adjacent cells; each hemi channel is a hexamer of connexin, a protein present in several isoforms in different cell types. An important property of connexins is their susceptibility to be reconstituted into unilamellar phospholipid liposomes where they feature transport properties as individual homomeric or heteromeric hemi channels. Several known blockers of gap junctional channels or hemi channels (18 ß-glycyrrhetinic acid, lanthanum, octanol, and oleamide) afforded a marked ( 70%) inhibition of NAD⁺ influx into native 3T3 fibroblasts.

4. Connexin 43 (Cx43) plays a role in transmembrane NAD⁺ transport
Murine 3T3 fibroblasts constitutively express connexin 43 (Cx43); expression of this connexin isoform in Cx43-negative HeLa clones (most HeLa cell clones are Cx43-positive) has recently been reported to be induced by treatment of the cells with 5-aza-2'-deoxycytidine, an inhibitor of DNA methylation. Incubation of a specific HeLa clone lacking NAD⁺ transport activity with increasing concentrations of 5-aza-2'-deoxycytidine restored transmembrane NAD⁺ transport in a concentration-dependent fashion, with parallel de novo expression of Cx43. This result strongly suggested involvement of Cx43 in NAD⁺ transporting activity: thus, we designed experiments aimed at specifically inhibiting Cx43 functions: 1) in intact 3T3 fibroblasts, with an antisense oligodeoxynucleotide, and 2) in 3T3 membrane protein-reconstituted proteoliposomes, with a monoclonal antibody (mAb) raised to Cx43. Incubation of 3T3 cells with the antisense oligodeoxynucleotide abrogated the NAD⁺-releasing activity completely, whereas the corresponding sense oligodeoxynucleotide had no effect. Addition of the anti-Cx43 mAb during reconstitution of 3T3 membrane proteins into liposomes resulted in undetectable NAD⁺ influx into the proteoliposomes. Conversely, an anti-Cx26 mAb was totally ineffective.

5. Proteoliposomes reconstituted with purified Cx43 feature NAD⁺ transporting activity
To demonstrate that Cx43 is directly responsible for NAD⁺ transport, we purified this protein from solubilized 3T3 cell membranes. After a two-step affinity chromatography, the fraction exhibiting NAD⁺ transporting activity by the proteoliposome assay was adsorbed onto an immobilized polyclonal antiserum against Cx43. Silver staining of the final eluate showed a major band at 86 kDa and a lighter doublet at 44–47 kDa (Fig. 2 , lane 1). An identical pattern was observed upon staining the trans blot with the polyclonal anti-Cx43 antiserum (Fig. 2 , lane 2).Thus, the electrophoretically homogeneous protein, which was purified 43,000-fold from the solubilized cell membranes, can be identified as homodimeric Cx43 with a minor amount of monomeric form present as a typical doublet arising from its variable phosphorylation. The presence of both monomeric and dimeric sodium dodecyl sulfate (SDS) -polyacrylamide gel electrophoresis bands is a common feature of immunoaffinity-purified connexin proteins having hemi channel-sized structures. Upon phospholipid reconstitution of the anti-Cx43 immunoaffinity eluate, the proteoliposomes acquired NAD⁺ transporting activity (Fig. 2b ), thus proving unequivocally that Cx43 is directly responsible for NAD⁺ transport. No transport of cyclic ADP-ribose (cADPR) or of ADP-ribose was detectable with the same Cx43-reconstituted proteoliposomes. Specificity of Cx43 was demonstrated by failure to recover any protein and any NAD⁺ transporting activity upon performing the final immunopurification step on an anti-Cx32 polyclonal antiserum rather than on anti-Cx43 (Fig. 2b ).

View larger version (28K): [in this window] [in a new window]   Figure 2. Connexin isoform-specific NAD+ transporting activity in proteoliposomes reconstituted with homogeneous Cx43. a) SDS electrophoretic patterns of purified Cx43 detected either by silver staining (lane 1) or with an anti-Cx43 antibody (lane 2). b) NAD+ transporting activity was measured in proteoliposomes reconstituted either with the Cx43 preparation shown in panel A or with an eluate from Sepharose-bound anti-Cx32 polyclonal antibody. cADPR and ADP-ribose, both added at 5 mM, did not permeate across these proteoliposomes.

CONCLUSIONS AND SIGNIFICANCE

Our findings lead us to conclude that Cx43 hemi channels mediate a regulatable dinucleotide transport across cell membranes. Transport inhibition experiments and the failure to detect any influx of two metabolically related nucleotides, cADPR and ADP-ribose, suggest some specificity of dinucleotide transport. This is the first evidence that connexin hemi channels can directly mediate transmembrane fluxes of a nucleotide in whole cells.

Properties of the transmembrane NAD⁺ transporter, here identified with Cx43, and especially its equilibrative nature of gradient-directed transport system, leave little doubt on the prevalence of release of NAD⁺ from cells over its influx from extracellular fluids where NAD⁺ concentrations are as low as 10–40 nM. Therefore, potential Cx43-mediated NAD⁺ leakage from intact cells raises questions about the in vivo significance of an apparently wasteful loss of cellular dinucleotide and about requirement of some regulatory mechanisms to prevent it. Recent findings on the 3-dimensional structure of gap junction channel composed by two Cx43 hemi channels have revealed a part of non--helical structure at the extracellular region, suggesting the possibility of a tight seal between the channel pore and the extracellular environment. Our present data demonstrate that bidirectional NAD⁺ transport across Cx43 hemi channels can be reversibly regulated, e.g., by Ca²⁺ concentration (Fig. 1) . This property might be of physiological significance, being related to the only reported role of the NAD⁺ transporting structure, i.e., its functional interaction with the transmembrane glycoprotein CD38. This is a widely expressed bifunctional ectoenzyme acting on NAD⁺ as substrate and involved in the metabolism of the potent calcium releaser and universal second messenger cADPR. The interplay between the NAD⁺ transport system and CD38 has been shown to functionally overcome the compartmentation of the CD38 active site that otherwise would be inaccessible to cytosolic NAD⁺. This topological restriction holds for any known membrane localization of CD38, both to the plasma membrane and to the intracellular vesicles arising either from exocytosis or from endocytosis. Thus, especially under conditions of ligand-dependent endocytosis of CD38 (and of NAD⁺ transporter as well), an intensified subcellular trafficking of NAD⁺ and cADPR results in a sustained and remarkable increase of [Ca²⁺]_i. Inhibition of Cx43-mediated NAD⁺ transport via enhanced [Ca²⁺]_i (Fig. 1a ) and consequent switch-off of CD38/ADP-ribosyl cyclase activity might therefore represent a feedback mechanism designed to down-regulate potentially detrimental, cADPR-mediated increases of [Ca²⁺]_i. In addition to this mechanism, however, other modulators of NAD⁺ transport could exist in view of known susceptibility of connexin hemi channels to phosphorylation, voltage, and cyclic nucleotides.

Besides qualifying as an autocrine system for finely tuning intracellular calcium levels in cADPR-responsive cells, the presence of a NAD⁺ transporter on cell membranes might more generally enable the generation and propagation of intercellular waves of this dinucleotide for the triggering or amplification of NAD⁺-dependent processes either in adjacent cells or at distance (Fig. 3 ). Thus, Cx43 hemi channels seem to play a role in the NAD⁺-mediated paracrine regulation of a wide number of cellular processes, ranging from Ca²⁺-stimulated events (e.g., expansion of human hemopoietic progenitors) to dehydrogenase reactions, (mono)-ADP-ribosylation of proteins, and (poly)-ADP-ribosylation-dependent mechanisms of DNA repair.

View larger version (21K): [in this window] [in a new window]   Figure 3. Schematic picture of connexin 43 hemi channels mediating release of intracellular NAD+ from intact cells. Cx43 hemi channels behave as pores whose NAD+ transporting function can be reversibly regulated, e.g., inhibited by high extracellular and intracellular Ca2+ and by low pH. The NAD+ released into the medium can stimulate NAD+-dependent processes in other neighboring or distant cells (paracrine function) or act as substrate of ectoenzymes including CD38/ADP-ribosyl cyclase (that generates cADPR). Left: unrestricted NAD+ release. Center: NAD+ release under physiological conditions. Right: closure of NAD+-releasing Cx43 hemi channels at high extracellular and intracellular Ca2+ and low pH.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.00-0566fje To cite this article, use (November 9, 2000) FASEB J. 10.1096/fj.00-0566fje

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