Syntrophin

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Stanley C. Froehner - One of the best experts on this subject based on the ideXlab platform.

  • Targeted deletion of β1-Syntrophin causes a loss of Kir 4.1 from Müller cell endfeet in mouse retina.
    Glia, 2019
    Co-Authors: Shreyas Balachandra Rao, Marvin E Adams, Stanley C. Froehner, Shirin Katoozi, Nadia Skauli, Ole Petter Ottersen, Mahmood Amiry-moghaddam
    Abstract:

    Proper function of the retina depends heavily on a specialized form of retinal glia called Muller cells. These cells carry out important homeostatic functions that are contingent on their polarized nature. Specifically, the Muller cell endfeet that contact retinal microvessels and the corpus vitreum show a tenfold higher concentration of the inwardly rectifying potassium channel Kir 4.1 than other Muller cell plasma membrane domains. This highly selective enrichment of Kir 4.1 allows K+ to be siphoned through endfoot membranes in a special form of spatial buffering. Here, we show that Kir 4.1 is enriched in endfoot membranes through an interaction with β1-Syntrophin. Targeted disruption of this Syntrophin caused a loss of Kir 4.1 from Muller cell endfeet without affecting the total level of Kir 4.1 expression in the retina. Targeted disruption of α1-Syntrophin had no effect on Kir 4.1 localization. Our findings show that the Kir 4.1 aggregation that forms the basis for K+ siphoning depends on a specific Syntrophin isoform that colocalizes with Kir 4.1 in Muller endfoot membranes.

  • Syntrophin binds directly to multiple spectrin like repeats in dystrophin and mediates binding of nnos to repeats 16 17
    Human Molecular Genetics, 2018
    Co-Authors: Marvin E Adams, Jeffrey S. Chamberlain, Guy L Odom, Min Jeong Kim, Stanley C. Froehner
    Abstract:

    Mutation of the gene encoding dystrophin leads to Duchenne and Becker muscular dystrophy (DMD and BMD). Currently, dystrophin is thought to function primarily as a structural protein, connecting the muscle cell actin cytoskeleton to the extra-cellular matrix. In addition to this structural role, dystrophin also plays an important role as a scaffold that organizes an array of signaling proteins including sodium, potassium, and calcium channels, kinases, and nitric oxide synthase (nNOS). Many of these signaling proteins are linked to dystrophin via Syntrophin, an adapter protein that is known to bind directly to two sites in the carboxyl terminal region of dystrophin. A search of the dystrophin sequence revealed three additional potential Syntrophin binding sites (SBSs) within the spectrin-like repeat (SLR) region of dystrophin. Binding assays revealed that the site at SLR 17 bound specifically to the α isoform of Syntrophin while the site at SLR 22 bound specifically to the β-Syntrophins. The SLR 17 α-SBS contained the core sequence known to be required for nNOS-dystrophin interaction. In vitro and in vivo assays indicate that α-Syntrophin facilitates the nNOS-dystrophin interaction at this site rather than nNOS binding directly to dystrophin as previously reported. The identification of multiple SBSs within the SLR region of dystrophin demonstrates that this region functions as a signaling scaffold. The signaling role of the SLR region of dystrophin will need to be considered for effective gene replacement or exon skipping based DMD/BMD therapies.

  • b2-Syntrophin is a Cdk5 substrate that restrains the motility of insulin secretory granules
    2016
    Co-Authors: Ra Schubert, Marvin E Adams, Stanley C. Froehner, Klaus Peter Knoch, Joke Ouwendijk, Shabaz Mohammed, Yury Bodrov, Carolin Wegbrod, Yong Kim, Ole N
    Abstract:

    The molecular basis for the interaction of insulin granules with the cortical cytoskeleton of pancreatic b-cells remains unknown. We have proposed that binding of the granule protein ICA512 to the PDZ domain of b2-Syntrophin anchors granules to actin filaments and that the phosphorylation/dephosphorylation of b2-Syntrophin regulates this association. Here we tested this hypothesis by analyzing INS-1 cells expressing GFP-b2-Syntrophin through the combined use of biochemical approaches, imaging studies by confocal and total internal reflection fluorescence microscopy as well as electron microscopy. Our results support the notion that b2-Syntrophin restrains the mobility of cortical granules in insulinoma INS-1 cells, thereby reducing insulin secretion and increasing insulin stores in resting cells, while increasing insulin release upon stimulation. Using mass spectrometry, in vitro phosphorylation assays and b2-Syntrophin phosphomutants we found that phosphorylation of b2-Syntrophin on S75 near the PDZ domain decreases its binding to ICA512 and correlates with increased granule motility, while phosphorylation of S90 has opposite effects. We further show that Cdk5, which regulates insulin secretion, phosphorylates S75. These findings provide mechanistic insight into ho

  • The Light Chains of Microtubule-Associated Proteins MAP1A and MAP1B Interact with a1-Syntrophin in the Central and Peripheral Nervous System
    2016
    Co-Authors: Heike Fuhrmann-stroissnigg, Stanley C. Froehner, Douglas E Albrecht, Rainer Noiges, Luise Descovich, Irmgard Fischer, Fatiha Nothias, Friedrich Propst
    Abstract:

    Microtubule-associated proteins of the MAP1 family (MAP1A, MAP1B, and MAP1S) share, among other features, a highly conserved COOH-terminal domain approximately 125 amino acids in length. We conducted a yeast 2-hybrid screen to search for proteins interacting with this domain and identified a1-Syntrophin, a member of a multigene family of adapter proteins involved in signal transduction. We further demonstrate that the interaction between the conserved COOH-terminal 125-amino acid domain (which is located in the light chains of MAP1A, MAP1B, and MAP1S) and a1-Syntrophin is direct and occurs through the pleckstrin homology domain 2 (PH2) and the postsynaptic density protein 95/disk large/ zonula occludens-1 protein homology domain (PDZ) of a1-Syntrophin. We confirmed the interaction of MAP1B and a1-Syntrophin by co-localization of the two proteins in transfected cells and by co-immunoprecipitation experiments from mouse brain. In addition, we show that MAP1B and a1-Syntrophin partially co-localize in Schwann cells of the murine sciatic nerve during postnatal development and in the adult. However, intracellular localization of a1-Syntrophin and other Schwann cell proteins such as ezrin and dystrophin-related protein 2 (DRP2) and the localization of the axonal node of Ranvier-associated protein Caspr1/paranodin were not affected in MAP1B null mice. Our findings add to a growing body of evidence that classical MAPs are likely to be involved in signal transduction not only by directly modulating microtubul

  • The FASEB Journal • FJ Express Full-Length Article Biglycan regulates the expression and sarcolemmal localization of dystrobrevin, Syntrophin, and nNOS
    2013
    Co-Authors: Mary Lynn Mercado, Stanley C. Froehner, Alison R. Amenta, Hiroki Hagiwara, Michael S. Rafii, Beatrice E. Lechner, Rick T. Owens, David J. Mcquillan, Justin R. Fallon
    Abstract:

    ABSTRACT The dystrophin-associated protein complex (DAPC) provides a linkage between the cytoskeleton and the extracellular matrix (ECM) and is also a scaffold for a host of signaling molecules. The constituents of the DAPC must be targeted to the sarcolemma in order to properly function. Biglycan is an ECM molecule that associates with the DAPC. Here, we show that biglycan null mice exhibit a mild dystrophic phenotype and display a selective reduction in the localization of �-dystrobrevin-1 and-2, �- and �1-Syntrophin, and nNOS at the sarcolemma. Purified biglycan induces nNOS redistribution to the plasma membrane in cultured muscle cells. Biglycan protein injected into muscle becomes stably associated with the sarcolemma and ECM for at least 2 wk. This injected biglycan restores the sarcolemmal expression of �-dystrobrevin-1 and-2, and �1- and �2-Syntrophin in biglycan null mice. We conclude that biglycan is important for the maintenance of muscle cell integrity and plays a direct role in regulating the expression and sarcolemmal localization of the intracellular signaling proteins dystrobrevin-1 and-2, �- and �1-Syntrophin and nNOS.

Marvin E Adams - One of the best experts on this subject based on the ideXlab platform.

  • Targeted deletion of β1-Syntrophin causes a loss of Kir 4.1 from Müller cell endfeet in mouse retina.
    Glia, 2019
    Co-Authors: Shreyas Balachandra Rao, Marvin E Adams, Stanley C. Froehner, Shirin Katoozi, Nadia Skauli, Ole Petter Ottersen, Mahmood Amiry-moghaddam
    Abstract:

    Proper function of the retina depends heavily on a specialized form of retinal glia called Muller cells. These cells carry out important homeostatic functions that are contingent on their polarized nature. Specifically, the Muller cell endfeet that contact retinal microvessels and the corpus vitreum show a tenfold higher concentration of the inwardly rectifying potassium channel Kir 4.1 than other Muller cell plasma membrane domains. This highly selective enrichment of Kir 4.1 allows K+ to be siphoned through endfoot membranes in a special form of spatial buffering. Here, we show that Kir 4.1 is enriched in endfoot membranes through an interaction with β1-Syntrophin. Targeted disruption of this Syntrophin caused a loss of Kir 4.1 from Muller cell endfeet without affecting the total level of Kir 4.1 expression in the retina. Targeted disruption of α1-Syntrophin had no effect on Kir 4.1 localization. Our findings show that the Kir 4.1 aggregation that forms the basis for K+ siphoning depends on a specific Syntrophin isoform that colocalizes with Kir 4.1 in Muller endfoot membranes.

  • Syntrophin binds directly to multiple spectrin like repeats in dystrophin and mediates binding of nnos to repeats 16 17
    Human Molecular Genetics, 2018
    Co-Authors: Marvin E Adams, Jeffrey S. Chamberlain, Guy L Odom, Min Jeong Kim, Stanley C. Froehner
    Abstract:

    Mutation of the gene encoding dystrophin leads to Duchenne and Becker muscular dystrophy (DMD and BMD). Currently, dystrophin is thought to function primarily as a structural protein, connecting the muscle cell actin cytoskeleton to the extra-cellular matrix. In addition to this structural role, dystrophin also plays an important role as a scaffold that organizes an array of signaling proteins including sodium, potassium, and calcium channels, kinases, and nitric oxide synthase (nNOS). Many of these signaling proteins are linked to dystrophin via Syntrophin, an adapter protein that is known to bind directly to two sites in the carboxyl terminal region of dystrophin. A search of the dystrophin sequence revealed three additional potential Syntrophin binding sites (SBSs) within the spectrin-like repeat (SLR) region of dystrophin. Binding assays revealed that the site at SLR 17 bound specifically to the α isoform of Syntrophin while the site at SLR 22 bound specifically to the β-Syntrophins. The SLR 17 α-SBS contained the core sequence known to be required for nNOS-dystrophin interaction. In vitro and in vivo assays indicate that α-Syntrophin facilitates the nNOS-dystrophin interaction at this site rather than nNOS binding directly to dystrophin as previously reported. The identification of multiple SBSs within the SLR region of dystrophin demonstrates that this region functions as a signaling scaffold. The signaling role of the SLR region of dystrophin will need to be considered for effective gene replacement or exon skipping based DMD/BMD therapies.

  • b2-Syntrophin is a Cdk5 substrate that restrains the motility of insulin secretory granules
    2016
    Co-Authors: Ra Schubert, Marvin E Adams, Stanley C. Froehner, Klaus Peter Knoch, Joke Ouwendijk, Shabaz Mohammed, Yury Bodrov, Carolin Wegbrod, Yong Kim, Ole N
    Abstract:

    The molecular basis for the interaction of insulin granules with the cortical cytoskeleton of pancreatic b-cells remains unknown. We have proposed that binding of the granule protein ICA512 to the PDZ domain of b2-Syntrophin anchors granules to actin filaments and that the phosphorylation/dephosphorylation of b2-Syntrophin regulates this association. Here we tested this hypothesis by analyzing INS-1 cells expressing GFP-b2-Syntrophin through the combined use of biochemical approaches, imaging studies by confocal and total internal reflection fluorescence microscopy as well as electron microscopy. Our results support the notion that b2-Syntrophin restrains the mobility of cortical granules in insulinoma INS-1 cells, thereby reducing insulin secretion and increasing insulin stores in resting cells, while increasing insulin release upon stimulation. Using mass spectrometry, in vitro phosphorylation assays and b2-Syntrophin phosphomutants we found that phosphorylation of b2-Syntrophin on S75 near the PDZ domain decreases its binding to ICA512 and correlates with increased granule motility, while phosphorylation of S90 has opposite effects. We further show that Cdk5, which regulates insulin secretion, phosphorylates S75. These findings provide mechanistic insight into ho

  • Adiponectin receptor 1 C-terminus interacts with PDZ-domain proteins such as Syntrophins.
    Experimental and molecular pathology, 2013
    Co-Authors: Markus Neumeier, Marvin E Adams, Stanley C. Froehner, Sabrina Krautbauer, Sandra Schmidhofer, Yvonne Hader, Kristina Eisinger, E. Eggenhofer, Wolfgang Mages, Christa Buechler
    Abstract:

    Adiponectin receptor 1 (AdipoR1) is one of the two signaling receptors of adiponectin with multiple beneficial effects in metabolic diseases. AdipoR1 C-terminal peptide is concordant with the consensus sequence of class I PSD-95, disc large, ZO-1 (PDZ) proteins, and screening of a liver yeast two hybrid library identified binding to β2-Syntrophin (SNTB2). Hybridization of a PDZ-domain array with AdipoR1 C-terminal peptide shows association with PDZ-domains of further proteins including β1- and α-Syntrophin (SNTA). Interaction of PDZ proteins and C-terminal peptides requires a free carboxy terminus next to the PDZ-binding region and is blocked by carboxy terminal added tags. N-terminal tagged AdipoR1 is more highly expressed than C-terminal tagged receptor suggesting that the free carboxy terminus may form a complex with PDZ proteins to regulate cellular AdipoR1 levels. The C- and N-terminal tagged AdipoR1 proteins are mainly localized in the cytoplasma. N-terminal but not C-terminal tagged AdipoR1 colocalizes with Syntrophins in adiponectin incubated Huh7 cells. Adiponectin induced hepatic phosphorylation of AMPK and p38 MAPK which are targets of AdipoR1 is, however, not blocked in SNTA and SNTB2 deficient mice. Further, AdipoR1 protein is similarly abundant in the liver of knock-out and wild type mice when kept on a standard chow or a high fat diet. In summary these data suggest that AdipoR1 protein levels are regulated by so far uncharacterized class I PDZ proteins which are distinct from SNTA and SNTB2.

  • a-Syntrophin Modulates Myogenin Expression in Differentiating Myoblasts
    2013
    Co-Authors: Min Jeong Kim, Marvin E Adams, Stanley C. Froehner, Sung Ho Hwang, Jeong A. Lim, Hye Sun
    Abstract:

    Background: a-Syntrophin is a scaffolding protein linking signaling proteins to the sarcolemmal dystrophin complex in mature muscle. However, a-Syntrophin is also expressed in differentiating myoblasts during the early stages of muscle differentiation. In this study, we examined the relationship between the expression of a-Syntrophin and myogenin, a key muscle regulatory factor. Methods and Findings: The absence of a-Syntrophin leads to reduced and delayed myogenin expression. This conclusion is based on experiments using muscle cells isolated from a-Syntrophin null mice, muscle regeneration studies in a-Syntrophin null mice, experiments in Sol8 cells (a cell line that expresses only low levels of a-Syntrophin) and siRNA studies in differentiating C2 cells. In primary cultured myocytes isolated from a-Syntrophin null mice, the level of myogenin was less than 50 % that from wild type myocytes (p,0.005) 40 h after differentiation induction. In regenerating muscle, the expression of myogenin in the a-Syntrophin null muscle was reduced to approximately 25 % that of wild type muscle (p,0.005). Conversely, myogenin expression is enhanced in primary cultures of myoblasts isolated from a transgenic mouse over-expressing a-Syntrophin and in Sol8 cells transfected with a vector to over-express a-Syntrophin. Moreover, we find that myogenin mRNA is reduced in the absence of a-Syntrophin and increased by a-Syntrophin over-expression. Immunofluorescence microscopy shows that a-Syntrophin is localized to the nuclei of differentiating myoblasts. Finally

Michael L Fitzgerald - One of the best experts on this subject based on the ideXlab platform.

  • lxr agonism upregulates the macrophage abca1 Syntrophin protein complex that can bind apoa i and stabilized abca1 protein but complex loss does not inhibit lipid efflux
    Biochemistry, 2015
    Co-Authors: Norimasa Tamehiro, Min Hi Park, Victoria Hawxhurst, Kamalpreet Nagpal, Marv E Adams, Vassilis I Zannis, Douglas T Golenbock, Michael L Fitzgerald
    Abstract:

    Macrophage ABCA1 effluxes lipid and has anti-inflammatory activity. The Syntrophins, which are cytoplasmic PDZ protein scaffolding factors, can bind ABCA1 and modulate its activity. However, many of the data assessing the function of the ABCA1–Syntrophin interaction are based on overexpression in nonmacrophage cells. To assess endogenous complex function in macrophages, we derived immortalized macrophages from Abca1+/+ and Abca1–/– mice and show their phenotype recapitulates primary macrophages. Abca1+/+ lines express the CD11B and F4/80 macrophage markers and markedly upregulate cholesterol efflux in response to LXR nuclear hormone agonists. In contrast, immortalized Abca1–/– macrophages show no efflux to apoA-I. In response to LPS, Abca1–/– macrophages display pro-inflammatory changes, including an increased level of expression of cell surface CD14, and 11–26-fold higher levels of IL-6 and IL-12 mRNA. Given recapitulation of phenotype, we show with these lines that the ABCA1–Syntrophin protein complex i...

  • LXR Agonism Upregulates the Macrophage ABCA1/Syntrophin Protein Complex That Can Bind ApoA‑I and Stabilized ABCA1 Protein, but Complex Loss Does Not Inhibit Lipid Efflux
    2015
    Co-Authors: Norimasa Tamehiro, Min Hi Park, Victoria Hawxhurst, Kamalpreet Nagpal, Marv E Adams, Vassilis I Zannis, Douglas T Golenbock, Michael L Fitzgerald
    Abstract:

    Macrophage ABCA1 effluxes lipid and has anti-inflammatory activity. The Syntrophins, which are cytoplasmic PDZ protein scaffolding factors, can bind ABCA1 and modulate its activity. However, many of the data assessing the function of the ABCA1–Syntrophin interaction are based on overexpression in nonmacrophage cells. To assess endogenous complex function in macrophages, we derived immortalized macrophages from Abca1+/+ and Abca1–/– mice and show their phenotype recapitulates primary macrophages. Abca1+/+ lines express the CD11B and F4/80 macrophage markers and markedly upregulate cholesterol efflux in response to LXR nuclear hormone agonists. In contrast, immortalized Abca1–/– macrophages show no efflux to apoA-I. In response to LPS, Abca1–/– macrophages display pro-inflammatory changes, including an increased level of expression of cell surface CD14, and 11–26-fold higher levels of IL-6 and IL-12 mRNA. Given recapitulation of phenotype, we show with these lines that the ABCA1–Syntrophin protein complex is upregulated by LXR agonists and can bind apoA-I. Moreover, in immortalized macrophages, combined α1/β2-Syntrophin loss modulated ABCA1 cell surface levels and induced pro-inflammatory gene expression. However, loss of all three Syntrophin isoforms known to bind ABCA1 did not impair lipid efflux in immortalized or primary macrophages. Thus, the ABCA1–Syntrophin protein complex is not essential for ABCA1 macrophage lipid efflux but does directly interact with apoA-I and can modulate the pool of cell surface ABCA1 stabilized by apoA-I

Hartmut Oschkinat - One of the best experts on this subject based on the ideXlab platform.

  • specific interactions between the Syntrophin pdz domain and voltage gated sodium channels
    Nature Structural & Molecular Biology, 1998
    Co-Authors: Johan Schultz, Ulrich Hoffmuuller, Jennifer Ashurst, Maria J Macias, Jens Schneidermergener, Gerd Krause, Peter Schmieder, Hartmut Oschkinat
    Abstract:

    Syntrophins are modular proteins belonging to the dystrophin associated glycoprotein complex and are thought to be involved in the regulation of the muscular system. Screening of peptide libraries revealed selectivity of the synotrophin PDZ domain toward the motif R/K/Q-E-S/T-X-V-COO− found to be highly conserved in the α-subunit C-terminus of vertebrate voltage gated sodium channels (VGSCs). The solution structure of the domain in complex with the peptide G-V-K-E-S-L-V shows specific interactions between the conserved residues in the peptide and Syntrophin-characteristic residues of the domain. We propose that Syntrophins localize VGSCs to the dystrophin network through its PDZ domain.

  • specific interactions between the Syntrophin pdz domain and voltage gated sodium channels
    Nature Structural & Molecular Biology, 1998
    Co-Authors: Johan Schultz, Ulrich Hoffmuuller, Jennifer Ashurst, Maria J Macias, Jens Schneidermergener, Gerd Krause, Peter Schmieder, Hartmut Oschkinat
    Abstract:

    Syntrophins are modular proteins belonging to the dystrophin associated glycoprotein complex and are thought to be involved in the regulation of the muscular system. Screening of peptide libraries revealed selectivity of the synotrophin PDZ domain toward the motif R/K/Q-E-S/T-X-V-COO− found to be highly conserved in the α-subunit C-terminus of vertebrate voltage gated sodium channels (VGSCs). The solution structure of the domain in complex with the peptide G-V-K-E-S-L-V shows specific interactions between the conserved residues in the peptide and Syntrophin-characteristic residues of the domain. We propose that Syntrophins localize VGSCs to the dystrophin network through its PDZ domain.

Shinichi Takeda - One of the best experts on this subject based on the ideXlab platform.

  • α1 Syntrophin deficient mice exhibit impaired muscle force recovery after osmotic shock
    Muscle & Nerve, 2014
    Co-Authors: Toshifumi Yokota, Takaaki Ikemoto, Yuko Miyagoesuzuki, Ryoichi Matsuda, Shinichi Takeda
    Abstract:

    Introduction: α1-Syntrophin, a member of the dystrophin complex, recruits membrane molecules, including aquaporin-4, at the sarcolemma. The physiological functions of α1-Syntrophin are poorly understood. Methods: We examined the physiological characteristics of α1-Syntrophin–deficient muscles under osmotic stress conditions to test the possibility that mutant muscles are less tolerant of osmotic shock. Results: Isolated muscle bundles from mutant mice showed markedly reduced force production after hypo-osmotic shock. In addition, the mutant muscle bundles showed delayed recovery of specific gravity after being exposed to hypo-osmotic conditions. Two consecutive exercise tests on the treadmill revealed their performance in the second test was significantly lower than for wild-type mice. Furthermore, mutant mice had higher serum lactate concentrations after treadmill exercise. Conclusions: Although the lack of α1-Syntrophin from the sarcolemma does not lead to muscle degeneration, our results suggest that it may be partly involved in the pathophysiology of dystrophin-deficient Duchenne muscular dystrophy. Muscle Nerve 49: 728–735, 2014

  • aquaporin 4 is absent at the sarcolemma and at perivascular astrocyte endfeet in α1 Syntrophin knockout mice
    Proceedings of the Japan Academy. Ser. B: Physical and Biological Sciences, 2000
    Co-Authors: Toshifumi Yokota, Shuhei Kameya, Yuko Miyagoe, Ryoichi Matsuda, Yukio Hosaka, Kayoko Tsukita, Seiji Shibuya, Yoshihiro Wakayama, Shinichi Takeda
    Abstract:

    α1-Syntrophin, a member of dystrophin-associated proteins, is expressed at the sarcolemma and at perivascular astrocytes, and participates in protein-protein interactions through its PDZ domain. Aquaporin-4 (AQP4) is the predominant water channel protein in the brain, and also expressed at the sarcolemma of fast-twitch muscle fibers. AQP4 is concentrated in orthogonal array particles (OAPs), and its expression has been reported to be decreased at the sarcolemma of dystrophin-deficient mdx mice. We examined whether α1-Syntrophin targets AQP4 at the sarcolemma. Immunohistochemistry showed that AQP4 is absent at the sarcolemma in α1-Syntrophin knockout mice and that its expression is also lost from the perivascular astrocyte endfeet. On the other hand, expression of AQP4 is not decreased at the sarcolemma of the knockout mice in the neonatal stage. Moreover, AQP4 is expressed in lung, stomach, and kidney of wild-type and α1-Syntrophin null mice. Our results show that α1-Syntrophin is a key molecule to localize AQP4 to the sarcolemma of mature fast myofibers and astrocyte endfeet, but AQP4 is targeted to the plasma membrane by different molecules in lung, stomach, and kidney.

  • α1 Syntrophin gene disruption results in the absence of neuronal type nitric oxide synthase at the sarcolemma but does not induce muscle degeneration
    Journal of Biological Chemistry, 1999
    Co-Authors: Shuhei Kameya, Yuko Miyagoe, Kazunori Hanaoka, Yo-ichi Nabeshima, Takaaki Ikemoto, Makoto Endo, Ikuya Nonaka, Shinichi Takeda
    Abstract:

    Abstract α1-Syntrophin is a member of the family of dystrophin-associated proteins and is strongly expressed in the sarcolemma and the neuromuscular junctions. All three Syntrophin isoforms have a PDZ domain that appears to participate in protein-protein interactions at the plasma membrane. α1-Syntrophin has additionally been shown to associate with neuronal nitric-oxide synthase (nNOS) through PDZ domains in vitro. These observations suggest that α1-Syntrophin may work as a modular adaptor protein that can link nNOS or other signaling enzyme to the sarcolemmal dystrophin complex. In the sarcolemma, nNOS regulates the homeostasis of reactive free radical species and may contribute to the oxidative damage to muscle protein in muscle disease such as Duchenne muscular dystrophy. In this study, we generated α1-Syntrophin knock-out mice to clarify the interaction between α1-Syntrophin and nNOS in the skeletal muscle. We observed that nNOS, normally expressed in the sarcolemma, was largely absent from the sarcolemma, but considerably remained in the cytosol of the knock-out mice. Even though the distribution of nNOS was altered, the knock-out mice displayed no gross histological changes in the skeletal muscle. We also discovered that muscle contractile properties have not been influenced in the knock-out mice.