Human Molecular Genetics, 2000, Vol. 9, No. 7 1033-1040
© 2000 Oxford University Press
Biochemical evidence for association of dystrobrevin with the sarcoglycan–sarcospan complex as a basis for understanding sarcoglycanopathy
1Department of Cell Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi-chou, Kodaira, Tokyo 187-8502, Japan and 2Inheritance and Variation Group, PREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan
Received 2 December 1999; Revised and Accepted 22 February 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The sarcoglycan complex is composed of four membrane-spanning dystrophin-associated proteins (DAPs) and is essential for skeletal muscle survival, since the absence or markedly reduced expression of this complex due to mutation of any one of the sarcoglycan genes causes a group of muscular dystrophies, collectively termed sarcoglycanopathy. Although one of the putative functions of the sarcoglycan complex is its participation in signaling processes, detailed studies have been scarce. Very recently, it was shown that gene knockout mice for a DAP,
-dystrobrevin, exhibit a dystrophic phenotype, possibly due to defects in muscle cell signaling. To clarify the putative function of the sarcoglycan complex, it is essential to determine whether or not there is a link between it and the intracellular signaling molecules. To elucidate this, we developed new methods for preparing various DAP complexes containing the sarcoglycan complex from the purified dystrophin–DAP complex. It was suggested from one of the complexes prepared that the sarcoglycan–sarcospan complex (the sarcoglycan complex associated with sarcospan) is associated with syntrophin and/or dystrobrevin. Further analysis of this complex revealed that the N-terminal half of dystrobrevin participates in this association. It is thus considered that the sarcoglycan–sarcospan complex is linked to the signaling protein neuronal nitric oxide synthase via -syntrophin associated with dystrobrevin. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Loss of dystrophin on the sarcolemma due to a mutation of its gene and the concomitant marked reduction in the expression of dystrophin-associated proteins (DAPs) causes Duchenne muscular dystrophy (DMD), which is inherited in an X-linked recessive mode. Previous studies (1–3) showed that dystrophin links the basement membrane with the subsarcolemmal cytoskeletal network, together with the membrane-spanning dystroglycan (DG) complex composed of two DAPs, termed
- and ß-DGs. Based on these results, it is generally agreed that the sarcolemma is coated fully by both the basement membrane and the subsarcolemmal cytoskeletal network and thus protected from mechanical stresses during muscle contraction (4–6).
The sarcoglycan (SG) complex is a membrane-spanning glycoprotein complex (1,5) composed of four DAPs, termed - to 
-SG. Absence or markedly reduced expression of this complex due to mutation of any one of the SG genes causes a group of muscular dystrophies with a Duchenne-like phenotype. These muscular dystrophies are inherited in an autosomal recessive mode and are collectively termed sarcoglycanopathy (SGP) (5). The SG complex was found initially, together with the DG complex and the dystrophin–syntrophin–dystrobrevin complex, by treatment of the dystrophin–DAP complex with n-octyl ß-D-glucoside (1). Whereas the structural role of the DG complex in the sarcolemma has been well defined, that of the SG complex remains unclarified, since it was not shown how the SG complex interacts with the remaining components in the dystrophin–DAP complex. Recent studies on SG gene knockout mice (7,8), together with previous studies on dystrophic hamsters (9,10), indicate that the marked reduction in the expression of the SG complex destabilizes, to some extent, the binding between - and ß-DGs and between ß-DG and dystrophin. The SG complex seems to strengthen the above-stated membrane-protecting system in which dystrophin and the DG complex participate. Therefore, it can be easily understood why SGP is pathophysiologically similar to DMD.
Besides the role of the SG complex in providing mechanical stability to the muscle cell, the possibility has been suggested that it also participates in signaling processes as a receptor, since ß- to -SGs have an epidermal growth factor (EGF) receptor-like motif near their C-termini (11). On the other hand, -syntrophin has been shown to be associated with neuronal nitric oxide synthase (nNOS), a signaling protein (12). Very recently, -dystrobrevin-deficient mice were found to exhibit a muscular dystrophy phenotype, and showed secondary loss of nNOS from the sarcolemma (13). To examine the putative signaling function of the SG complex, it is essential to clarify the structural relationship of the SG complex with the other members of the dystrophin–DAP complex, and to determine, if present, the link between the SG complex and the intracellular signaling molecules. In the present study, we developed new methods for preparing various novel DAP complexes containing the SG complex from the purified dystrophin–DAP complex. We show that the SG complex, which is associated with sarcospan (SPN), binds the N-terminal region of -dystrobrevin.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Preparation of the complexes including the SG complex
The first complex.
When the purified dystrophin–DAP complex was incubated at 37°C in 0.1 M NaCl with buffer A, containing 0.1% digitonin, 20 mM HEPES (pH 7.5), 0.5 mM dithiothreitol (DTT) and 0.7 mM benzamidine, and separated by gel chromatography, two peaks, P0 and P1, appeared (Fig. 1a). P1*, which was purified from P1 by rechromatography, was then examined by immunoblot analysis (Fig. 1b). It contained four SGs, SPN and two DGs, but no dystrophin,
- and ß1-syntrophins or dystrobrevin (Table 1), demonstrating that SGs, DGs and SPN form a tight complex even without the involvement of dystrophin.
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The second complex.
When the dystrophin–DAP complex was incubated at 37°C in 1 M NaCl with buffer A and separated by gel chromatography, a new peak fraction (P2), eluting more slowly than P1, was found (Fig. 1c). Immunoblot analysis revealed that P2 contained four SGs and significant amounts of syntrophins, dystrobrevin and SPN, but neither dystrophin nor ß-DG (Fig. 1d). Suspecting that P2 was contaminated with both syntrophins and dystrobrevin, we purified P2 by immunoprecipitation using anti--SG antibody (MA2-1). We found syntrophins, dystrobrevin and SPN as well as the four SGs in the precipitate (P2*), although the amounts of syntrophins and dystrobrevin were somewhat reduced (Fig. 1d and Table 1). Thus, P2* is the SG complex associated with SPN, syntrophins and/or dystrobrevin.
The third complex.
To remove both syntrophin and dystrobrevin from the second complex, we incubated P1 at 37°C in 1 M NaCl with buffer A and separated it by gel chromatography. We obtained a peak fraction (P3) like P2 (Fig. 1e). P3 only contained the four SGs and SPN, but no syntrophins, dystrobrevin or ß-DG (Fig. 1f and Table 1), indicating that this complex is the SG complex associated with SPN. Tight interaction between the SG complex and SPN was also suggested in a recent report (14), and raises the possibility that SPN is an additional member of the SG complex. We initially prepared the SG complex by treating the dystrophin–DAP complex with n-octyl ß-D-glucoside (1). However, we did not examine SPN in detail in that study. Therefore, we carefully re-examined the SG complex prepared with n-octyl ß-D-glucoside by immunoblot analysis and found that SPN was not detected in this preparation (data not shown). Thus, we consider that SPN is not an additional member of the SG complex. We term the third complex the SG–SPN complex.
Dystrobrevin interacts directly with the SG–SPN complex
With respect to the second complex, it remains unclear whether syntrophin or dystrobrevin is associated with the SG–SPN complex. Previously, we analyzed the protein fragments generated by partial digestion of the dystrophin–DAP complex with calpain and made the important finding that the binding locus for the glycoprotein complex composed of DGs and SGs on dystrophin was confined to the small region spanning the cysteine-rich and the first half of the C-terminal domains (15). In this study, analysis of the DAPs was carried out mostly by protein staining, since their specific antibodies were not available. Since the protein staining intensities of dystrobrevin, previously named A0, and SPN were much weaker than those of other DAPs, these proteins could not be analyzed in detail. In the present study, we re-examined the above-mentioned digests in order to analyze the second complex more precisely, with special attention to dystrobrevin. To this end, it was necessary to characterize the antibodies for dystrobrevin (DB-a, -b and -c) (Fig. 2a). In human adult skeletal muscles, three predominant alternatively spliced isoforms of -dystrobrevin are expressed (16). In the same tissues, ß-dystrobrevin, encoded by a different gene, is also expressed, but in low amounts (17,18). Based on the sequence of the fusion proteins used for the antigen, it is considered that DB-c is specific for -dystrobrevin-1, whereas DB-a and -b may cross-react with ß-dystrobrevin because of the sequence homology (17–19). However, we consider that the dystrobrevins present in the dystrophin–DAP complex are most likely to be of the -type, because it has been reported that, whereas -dystrobrevin is immunoprecipitated together with syntrophins by the pan-specific anti-syntrophin antibody from Triton-X-100-extracted skeletal muscle, ß-dystrobrevin is not (18).
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We found that DB-a, -b and -c reacted with three, two and one of the bands, respectively (Fig. 2b). We thus consider that DB-a, -b and -c, in that order, recognize the N-terminal region common to the three isoforms, the intermediate region excluding
-dystrobrevin-3, and the C-terminal region specific to -dystrobrevin-1. Furthermore, taking into consideration their molecular masses, it is very likely that the three bands recognized by DB-a are coincident, in descending order, with -dystrobrevin-1, -2 and -3, respectively. However, we cannot exclude the possibility that the 40 kDa bottom band is the N-terminal fragment generated by the degradation of -dystrobrevin-1 and -2. Since not only -dystrobrevin-1 and -2, which have the dystrophin-binding coiled-coil motif (20), but also the 40 kDa dystrobrevin, which lacks this motif, are included in the dystrophin–DAP complex, we assume that -dystrobrevin isoforms have an additional, as yet unknown, anchoring site present on their common N-terminal region.
Using these and other antibodies, we examined the calpain-generated digests of the dystrophin–DAP complex by immuno- blot analysis and found that -dystrobrevin as well as dystrophin were degraded by calpain, whereas other DAPs were not degraded to any appreciable extent (Fig. 2c). With respect to dystrobrevin, we found fragments (of 38 kDa and slightly smaller) detected only by DB-a, demonstrating that they were derived from the N-terminal region common to -dystrobrevin isoforms. On the basis of the fragment size (38 kDa), it is assumed that the cleavage site(s) exists in the locus not too far away from the C-terminal edge of the common region. By fractionation of the digests by wheat germ agglutinin (WGA) affinity chromatography, we observed that SGs, DGs and a group of dystrophin fragments recognized by the anti-dystrophin antibody P33c were recovered in the bound fraction, whereas most syntrophins were recovered in the unbound fraction (Fig. 2d). These results were consistent with those reported by us previously (15). However, we found that the dystrobrevin fragments as well as SPN were recovered in the WGA-bound fraction. Since dystrobrevin and SPN are not glycoproteins (21–23), these results show that dystrobrevin interacts directly with the SG–SPN complex and/or the DG complex.
To define this interaction further, we incubated the WGA-bound fraction of calpain-generated digests at 37°C in 1 M NaCl with buffer A and separated a fraction corresponding to the second complex by gel chromatography. We further purified the fraction by immunoprecipitation with anti--SG antibody and analyzed it by immunoblotting. As shown in Figure 3, dystrobrevin fragments were detected in this sample despite the absence of ß-DG. We thus conclude that dystrobrevin is associated with the SG–SPN complex at the N-terminal region.
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The putative
-dystrobrevin-3 is absent from the muscles of ß-SG gene knockout miceRecently, we generated a ß-SG gene knockout mouse (8) and showed that none of the four SGs was detected in its skeletal muscles. To examine how
-dystrobrevin is expressed in this mouse, we examined its skeletal muscles immunohistochemically. We found that the sarcolemma was stained with DB-b which reacts with both -dystrobrevin-1 and -2, as was the case for the wild-type mouse (Fig. 4a and b). A similar result was obtained with the -dystrobrevin-1-specific antibody DB-c (Fig. 4c and d). In addition, we prepared a light microsomal fraction and the WGA-bound fraction of digitonin extract from the skeletal muscles and examined them by immunoblotting. As shown in Figure 4e, DB-a detected three bands similar to those of rabbit dystrobrevin in the muscle of wild-type mouse, whereas in that of the knockout mouse, DB-a detected only the top two bands but not the bottom band, the putative -dystrobrevin-3.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In the present study, we developed new methods to prepare various types of DAP complex and obtained the following four complexes composed of: (i) DGs, SGs and SPN; (ii) SGs, SPN and syntrophin/dystrobrevin; (iii) SGs and SPN; and (iv) SGs, SPN and the N-terminal fragments of dystrobrevin. These results show that the SG complex is associated with SPN, and that the SG–SPN complex is associated with dystrobrevin in one case, and with the DG complex in another. The first and the second complexes were obtained under low and high salt conditions, respectively. It is thus suggested that electrostatic and hydrophobic interactions prevail in the associations between DGs and the SG–SPN complex, and between the SG–SPN complex and syntrophins/dystrobrevin, respectively. On the other hand, the association between SPN and the SG complex seems to be very tight, since it was maintained even after repeated heating of the first complex in 1 M NaCl. A strong interaction between SPN and the SG complex was also described in a recent report (14). These facts raise the question of whether SPN is an additional component of the SG complex, and is required for the complex formation. We do not think that this is the case, for the following reasons. (i) When the dystrophin–DAP complex is treated with n-octyl ß-D-glucoside, the SG complex is eluted separately from SPN. (ii) SGs are synthesized in the rough endoplasmic reticulum of C2C12 cells and immediately form a complex. The SG complex becomes associated with SPN after being transported to the Golgi complex (24). (iii) The molecular structures between SGs and SPN are quite different, taking into consideration the primary structures (5,25).
Among the above four complexes, the most important is that composed of the SGs, SPN and the N-terminal fragments of dystrobrevin. Three predominant isoforms of -dystrobrevin are known to be expressed in muscle, and they have a common N-terminal region followed by various sizes of the C-terminal region. Although -dystrobrevin-1 and -2 have a binding site for dystrophin, the smallest isoform -dystrobrevin-3 does not (16). Our biochemical findings showed that the -dystrobrevin isoforms are associated with the SG–SPN complex on the N-terminal region common to these isoforms. On the basis of this finding, we deduce that -dystrobrevin-1 and -2 span the SG complex and dystrophin (Fig. 5), whereas -dystrobrevin-3 is only associated with the SG complex. This prediction was supported by our present findings in the muscles of the ß-SG gene knockout mice that -dystrobrevin-1 and -2 were present on the sarcolemma despite the almost complete absence of the SG complex (8), whereas the putative -dystrobrevin-3 was lost selectively. In other words, these findings suggest that -dystrobrevin-1 and -2 can be present on the sarcolemma even in the absence of the anchoring SG complex, when dystrophin is present. In the SGP muscles, reduced expression of dystrobrevin was reported by Metzinger et al. (26). -dystrobrevin in these cases might be partially degraded in such a way that it loses its ability to bind to dystrophin.
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Another report by Rafael et al. (27) may also be understood based on our present findings together with those of previous reports. They showed in their report that DAPs such as syntrophins, ß-DG and SGs are normally expressed in the muscles of transgenic/mdx mice expressing dystrophin that lacks the region encoded by exons 71–74, which spans the syntrophin-binding site and a major part of the dystrobrevin-binding coiled-coil motif (20,28–30). In mdx mice, dystrophin is absent due to a gene mutation, and the expression of DAPs including both DGs and SGs is reduced secondarily. Recovery of the DAPs by expression of the mutant dystrophin may be explained as follows. The above-mentioned mutant dystrophin increases the amount of the DG complex, since a binding domain encoded by exons 61–67 is created (3). This mutant dystrophin also increases the amount of the SG–SPN complex, since there is a tight interaction between the DGs and the SG–SPN complexes, which was shown in the present study (the first complex) and also in other reports (31,32). Thus, the binding site for dystrobrevin on the SG–SPN complex is created and, in turn, the binding site for syntrophin present on
-dystrobrevin-1 and -2 (33) is created.
In normal muscles, one molecule of syntrophin is associated at the C-terminal region that is conserved among its isoforms (34) with one molecule each of dystrophin and -dystrobrevin-1 or -2 (Fig. 5). On the other hand, -syntrophin is associated at its PDZ domain present in the N-terminal region with the signaling protein nNOS (12). In fact, we detected nNOS in our purified dystrophin–DAP complex by immunoblot analysis. However, its content seems to be very low, since we could not detect the nNOS in the same complex by protein staining (M. Yoshida and E. Ozawa, unpublished data). In any case, our present results suggest that the SG complex is linked to nNOS via -syntrophin fixed to -dystrobrevin-1 or -2 (Fig. 5). In DMD and the mdx mouse, nNOS was reported to be displaced from the sarcolemma (35). In the -dystrobrevin gene knockout mice reported recently, nNOS was displaced from the sarcolemma, and dystrophic phenotypes were observed (13). Interestingly, in the mdx mouse, it was shown that the normal ability of skeletal muscle contraction to attenuate -adrenergic vasoconstriction is impaired, since NO is not provided from the sarcolemma to the surrounding arteries (36). However, in the case of the -syntrophin gene knockout mice, the normal muscle phenotype was observed, despite the displacement of nNOS from the sarcolemma (37).
In the SGP muscle, nNOS is preserved at the sarcolemma (35). We observed that nNOS was also preserved in the ß-SG gene knockout mice (K. Araishi and E. Ozawa, unpublished data). One of the putative functions of the SG complex is its participation in signaling processes as a receptor, since ß-, 
- and -SGs are known to have an EGF receptor-like motif close to their C-termini (11). It is tempting to propose that a certain signal to the SG complex is transmitted to nNOS via -syntrophin fixed to -dystrobrevin and regulates the activity of nNOS. We speculate that the absence of the SG complex in the muscles of SGP and the SG gene knockout mice impairs this regulation of nNOS activity and allows nNOS to produce excess NO, which causes damage to the muscle fibers. The nNOS activity is also regulated by membrane-integrated caveolin-3 (38), and gene defects of caveolin-3 cause muscular dystrophy (39,40) in which calf hypertrophy frequently is observed as in DMD and SGP.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Antibodies
MA2-1, MA4 (1) and NCL-b-SARC (NovoCastra, Newcastle-upon-Tyne, UK) were used to detect
-, - and ß-SGs, respectively, by immunoblotting. Both PA3a (1) and NCL-b-DG (NovoCastra) were used to detect ß-DG. Anti--DG antibody was purchased from Upstate Biotechnology (Lake Placid, NY). A polyclonal antibody for -SG was prepared by immunizing rabbits with the same antigen, as reported previously (8). Rabbit polyclonal antibodies to SPN were prepared against the synthetic polypeptide corresponding to the 27 C-terminal residues of human KRAG (41) coupled to bovine serum albumin (BSA) at an internal cysteine. Three types of affinity-purified antibody were raised for syntrophins. The fusion proteins used for immunogens correspond to the regions spanning amino acids 169–345 (PSyn) of human -syntrophin (28), and 195–378 (Pß1Syn) and 111–207 (pan-specific, PSyns) of human ß1-syntrophin (42). Three types of antibody for dystrobrevin were used, including a monoclonal antibody (D63020, DB-a) purchased from Transduction Laboratories (Lexington, KY). The other two were affinity-purified rabbit antibodies (DB-b and DB-c) raised for the present study. The fusion proteins used as the immunogens corresponded to the regions spanning amino acids 249–403 (DB-a) of mouse -dystrobrevin-1 (21), and 302–543 (DB-b) and 579–686 (DB-c) of human -dystrobrevin-1 (22). Since DB-b seemed to exhibit weak immunoreactivities against -dystrobrevin-3, we purified it further as follows. The fusion protein corresponding to this isoform from which the last nine isoform-specific amino acids were deleted (16) was prepared. An SDS extract of Escherichia coli expressing this fusion protein was separated by SDS–PAGE and transferred to Immobilon P (Millipore, Bedford, MA). The band corresponding to the fusion protein was excised and allowed to react with DB-b at 4°C overnight. The DB-b purified in this way exhibited negligible immunoreactivities against -dystrobrevin-3. P33c (15) or NCL-DYS2 (NovoCastra) was used for dystrophin. P33c is an antiserum against the region encoded by a part of exon 70.
Immunoprecipitation
The IgG fraction of MA2-1 or affinity-purified rabbit polyclonal -SG antibody (8) was fixed with the Affi-Gel Hz immunoaffinity kit (Bio-Rad, Hercules, CA). The SG complex fractions prepared by heat treatment of the samples were incubated overnight at 4°C with the gel equilibrated in 0.15 M NaCl with buffer A, containing 0.1% digitonin, 20 mM HEPES (pH 7.5), 0.5 mM DTT and 0.7 mM benzamidine, in a Microspin column (Amersham Pharmacia Biotech, Tokyo, Japan), and the gel was collected by brief centrifugation. After the gel was washed with the equilibrating buffer, the bound fraction was eluted with 0.1% digitonin and 0.1 M glycine–HCl (pH 2.5).
Heat treatment of samples
The dystrophin–DAP complex was prepared in accordance with the method described previously (1). The complex was incubated at 37°C for 6 h in 0.1 or 1 M NaCl with buffer A and subjected to gel chromatography at 20°C on a Superose 6 (PC 3.2/30 or HR10/30) column (Amersham Pharmacia Biotech) equilibrated in 0.15 M NaCl with buffer A.
Calpain digestion of the dystrophin–DAP complex
Digestion with m-calpain (Sigma, St Louis, MO) and the subsequent WGA affinity chromatography were performed essentially in accordance with the method described previously (15).
Immunohistochemistry and the preparation of muscle samples from wild-type and ß-SG gene knockout mice
Serial cryosections (7 µm) of quadriceps femoris muscles from 4-week-old mice were analyzed by immunofluorescence as described previously (8). A light microsomal fraction and the WGA-bound digitonin extract of the corresponding muscles were prepared in accordance with the method described previously (8).
Electrophoresis and immunoblotting
SDS–PAGE and the subsequent transfer to Immobilon P for immunoblotting were performed using a PhastSystem with various types of PhastGels (Amersham Pharmacia Biotech). The blots were stained using an ECL detection kit (Amersham Pharmacia Biotech).
Other methods
Proteins were concentrated in a Centricon 30 or a Microcon 30 microconcentrator (Millipore). Protein concentration was determined using a Coomassie plus protein assay reagent (Pierce, Rockford, IL), with BSA as the standard.
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ACKNOWLEDGEMENTS |
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This work is supported by Grants for Health Science Research, for COE program and for Nervous and Mental Disorders (8A-1 and 11B-1) from the Ministry of Health and Welfare, and Grants from the Ministry of Education, Science, Sports and Culture, and the Science and Technology Agency, Japan. E.W. was supported by the Japan Health Sciences Foundation.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +81 42 346 1720; Fax: +81 42 346 1750; Email: yoshida@ncnp.go.jp
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REFERENCES |
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