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© The Rockefeller University Press,
0021-9525/1999//659 $5.00
The Journal of Cell Biology, Volume 147, Number 3,
, 1999 659-670
Original Article |
Cloning and Characterization of a Potassium-Dependent Sodium/Calcium Exchanger in Drosophila
njcolley{at}facstaff.wisc.edu
Sodium/calcium(-potassium) exchangers (NCX and NCKX) are critical for the rapid extrusion of calcium, which follows the stimulation of a variety of excitable cells. To further understand the mechanisms of calcium regulation in signaling, we have cloned a Drosophila sodium/calcium-potassium exchanger, Nckx30C. The overall deduced protein topology for NCKX30C is similar to that of mammalian NCKX, having five membrane-spanning domains in the NH2 terminus separated from six at the COOH-terminal end by a large intracellular loop. We show that NCKX30C functions as a potassium-dependent sodium/calcium exchanger, and is not only expressed in adult neurons as was expected, but is also expressed during ventral nerve cord development in the embryo and in larval imaginal discs. Nckx30C is expressed in a dorsal–ventral pattern in the eye-antennal disc in a pattern that is similar to, but broader than that of wingless, suggesting that large fluxes of calcium may be occurring during imaginal disc development. Nckx30C may not only function in the removal of calcium and maintenance of calcium homeostasis during signaling in the adult, but may also play a critical role in signaling during development.
Key Words: calcium • development • Drosophila • photoreceptor • signal transduction
© 1999 The Rockefeller University Press
IN resting cells, intracellular calcium concentration is maintained at 10–100 nM, and can rise up to tens of µM during stimulation (Peretz et al. 1994b; Bootman and Berridge 1995; Hardie 1996b). The precise control of spatial and temporal profiles of calcium is essential for cellular function, and prolonged elevation of cytosolic calcium can be toxic, leading to cell death (Berridge 1998; Berridge et al. 1998). Hence, proper calcium removal or sequestration after a transient rise in cytoplasmic calcium is vital to all cells. Calcium extrusion from cells is carried out by two classes of membrane proteins, ATP-driven calcium pumps and sodium/calcium exchangers (NCX).1 The latter are thought to be particularly important in cells that handle a large flux of calcium across their plasma membrane, such as cardiac myocytes and many neurons, including vertebrate photoreceptors (for review see Blaustein and Lederer 1999).
Exchangers function to lower and maintain intracellular calcium at or below 100 nM by using the transmembrane (TM) sodium gradient as an energy source. Of the two well-characterized families of mammalian sodium/calcium (Na+/Ca2+) exchangers, one family, NCX, utilizes a stoichiometry of 3Na+/1Ca2+ and has three isoforms (Nicoll et al. 1996b; Philipson et al. 1996). NCX-type exchangers are expressed in a variety of tissues including heart, kidney, brain, as well as smooth and skeletal muscle (Nicoll et al. 1996b). The second family, called potassium-dependent sodium/calcium exchangers (NCKX), uses both the inward sodium gradient and the outward potassium gradient to extrude calcium at a stoichiometry of 4Na+/1Ca2+,1K+ (Cervetto et al. 1989; Schnetkamp et al. 1989). NCKX-type exchangers appear to have a more limited tissue distribution, and have thus far only been characterized extensively in the outer segments of retinal rod photoreceptors (for reviews see Schnetkamp 1989; Lagnado and McNaughton 1990). Retinal rod NCKX1 has been cloned from several mammalian species and shown to be an NCKX after heterologous expression in HEK293 cells (Reiländer et al. 1992; Tucker et al. 1998; Cooper et al. 1999). It has been localized to the plasma membrane of rod photoreceptor outer segments (Haase et al. 1990; Reiländer et al. 1992). Analysis of the results obtained by the various genomic sequencing projects demonstrate that NCKX homologues are encoded by eukaryotic and prokaryotic genomes (Wilson et al. 1994; Schwarz and Benzer 1997). Although NCKX- and NCX-type exchangers display little overall amino acid sequence identity, they are thought to be evolutionarily related (Nicoll et al. 1996a; Schwarz and Benzer 1997).
Calcium plays an important role in phototransduction in both vertebrates and invertebrates. Both utilize rhodopsin-mediated, G protein–coupled cascades, but with some important differences. Illumination of vertebrate rod photoreceptors results in the closing of cGMP-gated cation channels, and thus hyperpolarization of the photoreceptor cell (Stryer 1986; Yau 1994). A dark equilibrium between calcium influx via cGMP-gated channels and calcium extrusion via NCKX1 is disrupted, and net extrusion of calcium through NCKX1 results. Cytosolic calcium then falls from a dark value of 500–600 nM to a value of <50 nM in bright light (Gray-Keller and Detwiler 1994; Sampath et al. 1998). This process mediates the process of light adaptation in both retinal rods and cones (Matthews et al. 1988; Nakatani and Yau 1988a).
In Drosophila, calcium changes in the opposite direction (see Fig. 1). Phototransduction occurs via a phospholipase C–mediated cascade, and illumination triggers the opening of the cation-selective channels. The photoreceptors depolarize and intracellular calcium rises to tens of µM (Peretz et al. 1994a; Ranganathan et al. 1994; Hardie 1995, Hardie 1996a,Hardie 1996b; Ranganathan et al. 1995; Zuker 1996). The mechanism that reduces calcium back to resting levels (100 nM) after illumination has not yet been identified, but may utilize an electrochemical exchanger which couples calcium release from the cell to the inward sodium gradient, as is the case in vertebrate rod photoreceptors (Yau and Nakatani 1984; Schnetkamp 1986; Lagnado et al. 1988; Lagnado and McNaughton 1990). In fact, sodium/calcium exchange has been measured in Drosophila as well as in other invertebrate photoreceptors, and is also thought to be critical in light-adaptation (Lisman and Brown 1972; Minke and Armon 1984; O'Day and Gray-Keller 1989; O'Day et al. 1991; Ranganathan et al. 1994; Hardie 1995; Bauer et al. 1999).
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Materials and Methods |
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Functional Analysis
The full-length Nckx30C cDNA was cloned into the novel insect cell vector pEIA as an EcoRI fragment, and this was used for the stable transfection of High Five insect cells as described (Farrell et al. 1998). High Five cells (BTI-TN-5B1-4) derived from Trichoplusia ni egg cell homogenates were purchased from Invitrogen. These cells do not display endogenous exchanger activity.
Potassium-dependent sodium/calcium exchange activity was measured in High Five cells transformed with Nckx30C cDNA. The cells were loaded with sodium via the sodium-potassium ionophore, monensin, in a medium containing high sodium, 150 mM NaCl, 80 mM sucrose, 0.05 mM EDTA, and 20 mM Hepes, pH 7.4, according to the methods described for rod outer segments (Schnetkamp et al. 1995). The ionophore was removed and the sodium-loaded cells were washed with and resuspended in 150 mM LiCl, 80 mM sucrose, 0.05 mM EDTA, and 20 mM Hepes, pH 7.4. The cells were diluted 10-fold in media containing 80 mM sucrose, 20 mM Hepes, pH 7.4, and either 150 mM KCl, 150 mM NaCl, or 150 mM LiCl. 45Ca uptake was initiated by addition of 35 µM CaCl2 and 1 µCi 45Ca. 45Ca uptake in High Five cells was measured with a rapid filtration method with the use of borosilicate glass fibers over a time-course of 5 min as described previously (Schnetkamp et al. 1991b). The ice-cold washing medium contained 140 mM KCl, 80 mM sucrose, 5 mM MgCl 2, 1 mM EGTA, and 20 mM Hepes, pH 7.4.
Northern Analysis
Total RNA was prepared from the heads and bodies of 0–7-d-old Drosophila w1118 and eya lines using the Ultraspec RNA isolation system (Biotecx). PolyA+ RNA was isolated by affinity chromatography on oligo(dT) cellulose columns using the FastTrack 2.0 System (Invitrogen, Inc.). PolyA+ RNA from third instar larvae and 0–24-h embryos (Canton S strain) was purchased from Clontech. PolyA+ RNA (10 µg) from each sample was run on a denaturing 0.9% agarose gel for 3 h 130V/cm. The gel was stained with ethidium bromide and photographed on a UV transilluminator. The mRNA was transferred overnight by capillary action in 20x saline sodium citrate (SSC) to a positively charged nylon membrane (Nytran Plus), and fixed by UV cross-linking. The membrane was probed with [32P]UTP antisense riboprobes (Maxiscript In Vitro Transcription kit; Ambion, Inc.). Four subclones of Nckx30C were constructed and used for riboprobe production; 1.3 kb BamHI-BamHI (5' end), 500 bp BamHI-ClaI (TM1–TM5), ClaI-ClaI (loop region), and ClaI-EcoRV (TM6–TM11) (see Fig. 4 A). The antisense and sense riboprobes were incubated with the membranes using the NorthernMax hybridization buffer (Ambion, Inc.), the membranes were washed with 0.2x SSC, 1% SDS at 65°C, and exposed to Kodak X-OMAT X-ray film (Eastman Kodak). All four antisense probes displayed the same labeling pattern. No signal was detected with the sense probes. A 250-bp mouse β-actin antisense riboprobe was used as a control for the amount of RNA loaded (Maxiscript In Vitro Transcription kit; Ambion, Inc.).
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In Situ Hybridization
Heads from the w1118 strain of flies were embedded in Tissue-Tek OCT Compound (Miles, Inc.) and frozen on dry ice. Eyes were fixed in 4% paraformaldehyde, infiltrated with 2.3 M sucrose, and frozen in liquid nitrogen according to methods described previously (Colley et al. 1991). In situ hybridizations were carried out on 14-µm head sections and 0.5-µm eye sections in 50% formamide, 5x SSC, 0.5 mg/ml sheared herring sperm DNA, 0.05 mg/ml heparin, 0.25% CHAPS, 0.1% Tween 20, 1 mg/ml yeast torula RNA, 1x Denhardt's, at 55°C overnight. Embryo and imaginal disc in situ hybridizations were carried out essentially as described in Panganiban et al. 1994. In brief, embryos (Canton S strain) were collected, dechorionated, fixed, and processed for in situ hybridization as described by Panganiban et al. 1994. Proteinase K was not used. Embryos were hybridized in 50% formamide, 5x SSC, 500 µg/ml sheared salmon sperm DNA, 0.1% Tween 20, 1 mg/ml glycogen. Hybridization was carried out at 55°C for 24–30 h. Probe concentrations were 90 ng/300 µl. The larval imaginal discs were dissected from crawling third-instar larvae, but left attached to the cuticle. The discs were fixed, permeabilized with proteinase K at 25 µg/ml for 3 min at room temperature, and postfixed. Probe concentrations were 120 ng/300 µl.
Digoxigenin-labeled sense and antisense riboprobes were generated by in vitro transciption of five DNA templates as recommended by the digoxigenin/UTP supplier (Boehringer Mannheim Corp.). Five Nckx30C cDNA probes were used: 1.3 kb BamHI-BamHI (5' end), 500 bp BamHI-ClaI (TM1–TM5), ClaI-ClaI (loop region), ClaI-EcoRV (TM6–TM11), and the full-length Nckx30C cDNA clone (see Fig. 4 A). Calx cDNA was provided by E. Schwarz (Columbia University, New York, NY) (Schwarz and Benzer 1997). Chaoptin cDNA was provided by D. Van Vactor (University of California, Berkeley) and S.L. Zipursky (University of California, Los Angeles, Los Angeles, CA) (Reinke et al. 1988). After transcription, the reaction mix was treated with DNase and the riboprobes were hydrolyzed in carbonate buffer for 2 min at 80°C. All riboprobes were quantified by analysis in denaturing 0.8% agarose gels and by dot blot analysis. All detection steps were as described in Tautz and Pfeifle 1989. All Nckx30C antisense probes showed the same labeling pattern. No signal was detected with the sense probes.
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NCKX30C Is an NCKX
We examined the functional properties of NCKX30C in High Five cells. The strategy for these experiments takes advantage of properties of both NCX and NCKX. First, NCX and NCKX are bidirectional in their ability to mediate both calcium efflux (forward exchange) and calcium influx (reverse exchange). The direction of transport is dictated by the direction of the TM sodium gradient. Normally, the inward sodium gradient removes calcium from the cell (forward exchange). However, when external sodium is removed, the outward sodium gradient drives calcium into the cell (reverse exchange). Therefore, we measured the properties of reverse exchange of NCKX30C by measuring 45Ca uptake in sodium-loaded cells. We tested for NCKX activity by using three different manipulations of the cation gradient that are known to prevent NCKX activity. The cells were loaded with sodium via the sodium-potassium ionophore, monensin, in a medium containing high sodium, according to the methods described for rod outer segments (Schnetkamp et al. 1995). The ionophore was removed and the sodium-loaded cells were washed with and resuspended in low sodium buffer as described in the Materials and Methods. The cells were diluted 10-fold in media containing 80 mM sucrose, and 20 mM Hepes, pH 7.4, and either 150 mM KCl, 150 mM NaCl, or 150 mM LiCl. 45Ca uptake was initiated by addition of 35 µM CaCl2 and 1 µCi 45Ca. The first condition causes the release of internal sodium by the action of monensin, a sodium(-potassium) selective ionophore. Fig. 5 A shows that 45Ca uptake by NCKX30C was strongly inhibited by the addition of monensin, thus demonstrating a requirement for intracellular sodium for calcium transport.
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A critical distinction between NCKX and NCX is that calcium influx via NCKX requires the presence of potassium, and lithium cannot substitute for potassium (Tsoi et al. 1998). In contrast, calcium influx via reverse exchange in NCX is the same in media containing potassium or lithium (Tsoi et al. 1998; Cooper et al. 1999). 45Ca uptake by NCKX30C requires potassium and was not observed in media containing lithium (Fig. 5 C). This result demonstrates that NCKX30C functions as an NCKX.
As negative controls, we subjected nontransformed High Five cells to the same 45Ca uptake experimental protocols described above: 45Ca uptake in media containing potassium was indistinguishable from that in media containing either sodium or lithium, showing that there is no endogenous NCX or NCKX activity in the cells (data not shown). The above results demonstrate that NCKX30C mediates potassium-dependent sodium/calcium exchange similar to that observed for NCKX1 and NCKX2 (Tsoi et al. 1998; Cooper et al. 1999).
Northern Blot Analysis
Northern blot analysis revealed an 8-kb transcript that is expressed in embryos and larvae (Fig. 6). In the adult, two transcripts of 8 kb and 10 kb were detected. Expression was detected predominately in the head. Transcripts present in the body may represent the thoracic ganglia or other components of the nervous system (Demerec 1994). The 8-kb and 10-kb transcripts were also detected in eya-1 mutant flies, which lack eyes, indicating that expression is not restricted to the eyes (Fig. 6).
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Discussion |
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A puzzling finding is that the photoreceptors in Drosophila express both NCKX30C and Calx exchangers. The NCKX exchangers have several unique features that make them well-suited for calcium extrusion during phototransduction. Illumination of Drosophila photoreceptors activates the phototransduction cascade leading to the opening of the cation-selective channels and an increase in the intracellular calcium (Fig. 1). In both flies and vertebrate photoreceptor cells, sodium influx contributes substantially to the inward current, potentially leading to elevated [Na+]inside (Coles and Orkand 1985; Nakatani and Yau 1988b; Hardie 1996b; Gerster 1997). As the cytosolic sodium concentration increases and reduces the TM sodium gradient, NCX exchangers, like Calx, are expected to reverse direction at much lower cytosolic sodium concentrations when compared with the potassium-dependent NCKX exchangers (Schnetkamp et al. 1991c). Therefore, the potassium-dependent exchangers will be better able to function in phototransduction under these conditions. The apparent redundancy could also be explained if the subcellular distribution of NCKX30C and Calx are very different, with each fulfilling distinct functions. A combination of immunocytochemistry with mutant analysis will assist in resolving these questions.
To date, the central focus of efforts in development of Drosophila has been on the identification of regulatory genes that control development, with the potential contribution of calcium signaling remaining largely unexplored. Notable exceptions include systems responsible for dorsal–ventral positional information, such as the dorsal protein in dorsal–ventral pattern information in the early embryo and the wingless pathway. It has been demonstrated that increased calcium can act as a second messenger in the signal transduction pathway leading to the nuclear localization of dorsal, a maternally inherited transcription factor (Kubota et al. 1993). Another signaling pathway that may utilize calcium is wingless. wingless, a member of the Wnt gene family, encodes a secreted glycoprotein that is involved in a complex variety of signaling events (Nusse and Varmus 1992; Cadigan and Nusse 1997). In vertebrate embryos, one of the two apparently distinct Wnt pathways can act through a G protein–mediated phosphatidylinositol signaling cascade, resulting in a release of intracellular calcium from inositol 1,4,5 trisphosphate (InsP3 )-sensitive stores (Moon et al. 1997; Slusarski et al. 1997a,Slusarski et al. 1997b). Here, we demonstrate that Nckx30C is expressed in a pattern similar to, but broader than that observed for wingless. Nckx30C expression would indicate that, most likely, a substantial calcium flux is occurring in these cells. In this study, we show that exchangers are expressed during development, indicating that they may not only function in the removal of calcium and maintenance of calcium homeostasis during signaling in the adult, but may also play critical roles in signaling events during embryogenesis and patterning of imaginal discs. The isolation of Nckx30C in Drosophila permits a genetic analysis of the in vivo role of calcium in modulating signaling pathways in Drosophila.
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Acknowledgments |
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This work was supported by the Medical Research Council of Canada (P.P.M. Schnetkamp), and National Institutes of Health grant EY08768, Retina Research Foundation, Howard Hughes Medical Institute, Foundation Fighting Blindness, Fight-For-Sight, and the Research to Prevent Blindness Foundation (N.J. Colley).
Submitted: 30 August 1999
Revised: 29 September 1999
Accepted: 29 September 1999
1.used in this paper: NCKX, potassium-dependent sodium/calcium exchanger(s); NCX, sodium/calcium exchanger(s); SSC, saline sodium citrate; TM, transmembrane
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