Absence of α-Syntrophin Leads to Structurally Aberrant Neuromuscular Synapses Deficient in Utrophin

Adams, Marvin E.; Kramarcy, Neal R.; Krall, Stuart P; Rossi, Susana G.; Rotundo, Richard L.; Sealock, Robert; Froehner, Stanley C.

doi:10.1083/jcb.150.6.1385

Cited by 212 publications

(242 citation statements)

References 59 publications

(99 reference statements)

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“…The ␣-Syn Ϫ/Ϫ mice used in this study have a relatively subtle structural defect; ␣-syntrophin is missing, but the other four syntrophin isoforms are still expressed (6). Moreover, the basic structure of the dystrophin-associated protein complex remains intact in ␣-Syn Ϫ/Ϫ mice, and only the population of AQP4 in perivascular astroglial end-feet is mislocalized (4).…”

Section: Discussionmentioning

confidence: 99%

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

Amiry-Moghaddam

Otsuka

Hurn

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The water channel AQP4 is concentrated in perivascular and subpial membrane domains of brain astrocytes. These membranes form the interface between the neuropil and extracerebral liquid spaces. AQP4 is anchored at these membranes by its carboxyl terminus to ␣-syntrophin, an adapter protein associated with dystrophin. To test functions of the perivascular AQP4 pool, we studied mice homozygous for targeted disruption of the gene encoding ␣-syntrophin (␣-Syn ؊/؊ ). These animals show a marked loss of AQP4 from perivascular and subpial membranes but no decrease in other membrane domains, as judged by quantitative immunogold electron microscopy. In the basal state, perivascular and subpial astroglial end-feet were swollen in brains of ␣-Syn ؊/؊ mice compared to WT mice, suggesting reduced clearance of water generated by brain metabolism. When stressed by transient cerebral ischemia, brain edema was attenuated in ␣-Syn ؊/؊ mice, indicative of reduced water influx. Surprisingly, AQP4 was strongly reduced but ␣-syntrophin was retained in perivascular astroglial end-feet in WT mice examined 23 h after transient cerebral ischemia. Thus ␣-syntrophin-dependent anchoring of AQP4 is sensitive to ischemia, and loss of AQP4 from this site may retard the dissipation of postischemic brain edema. These studies identify a specific, syntrophin-dependent AQP4 pool that is expressed at distinct membrane domains and which mediates bidirectional transport of water across the brain-blood interface. The anchoring of AQP4 to ␣-syntrophin may be a target for treatment of brain edema, but therapeutic manipulations of AQP4 must consider the bidirectional water flux through this molecule. C erebral edema is essentially a loss of water homeostasis entailing a net increase of water flux into the brain. The route of water influx in this life-threatening condition is unknown, and no efficient therapy exists. We have previously shown that the brain expresses a water channel molecule, AQP4, that is strongly enriched in those astrocyte membrane domains forming the interface between brain neuropil and extracerebral spaces filled with blood or cerebrospinal fluid (1-3). To determine whether the pools of AQP4 in these specialized membrane domains are responsible for the fast influx of water that occurs during the development of brain edema, one must specifically eliminate the perivascular and subpial pools of AQP4 while leaving other pools of AQP4 intact. This can be achieved by deletion of ␣-syntrophin (␣-syn), an adapter protein in the dystrophin-associated protein complex that is required for anchoring AQP4 at these specialized membrane domains (4). Mice homozygous for targeted disruption of the gene encoding ␣-syntrophin (␣-Syn Ϫ/Ϫ ) exhibit a marked reduction of AQP4 in perivascular and subpial membranes but not in other locations in brain, because total brain AQP4 protein content is not reduced (4).The first aim of the present study was to use ␣-Syn Ϫ/Ϫ mice to investigate whether a selective depletion of the perivascular AQP4 pool reduces the vol...

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Section: Discussionmentioning

confidence: 99%

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

Amiry-Moghaddam

Otsuka

Hurn

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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470

416

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“…In that case ∼50% central nuclei are observed, but little mononuclear infiltration was seen and the overall dystrophy is considerably less severe than in mdx. α-Syntrophin knockout mice show decreased sarcolemmal expression of α-dystrobrevin-2 and nNOS, but no myopathic symptoms (27); (28). Finally, α-dystrobrevin-1 has been shown to bind to the intermediate filament proteins desmuslin and syncoilin [Newey, 2001;Blake, 2002].…”

Section: Discussionmentioning

confidence: 99%

Biglycan regulates the expression and sarcolemmal localization of dystrobrevin, syntrophin, and nNOS

Mercado¹,

Amenta²,

Hagiwara³

et al. 2006

FASEB j.

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The dystrophin associated protein complex (DAPC) provides a linkage between the cytoskeleton and the extracellular matrix 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 extracellular matrix 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 α-dystrobrevin -1 and -2, α-and β1-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 extracellular matrix for at least two weeks. This injected biglycan restores the sarcolemmal expression of α-dystrobrevin-1 and -2, and β1-and β2-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, α-and β1-syntrophin and nNOS.

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“…Hindlimb suspension (unloading) causes muscle atrophy, delocalization, and posttranscriptional downregulation of nNOSμ protein to approximately 50% of wild-type levels (Tidball et al 1998;Suzuki et al 2007). Full nNOSμ expression requires its localization at the sarcolemma (Adams et al 2000). Suzuki et al (2007) reported that cytosolic nNOS activity is increased by unknown mechanisms and promotes hindlimb muscle atrophy through the activation of the forkhead transcription factor FoxO3 pathway (Figure 1).…”

Section: Inactivity-dependent Regulation Of Nnos Expression and Catalmentioning

confidence: 99%

“…Skeletal muscles express two alternatively spliced nNOS isoforms, nNOSμ and nNOSβ, both of which are expressed in fast and slow muscle types (Silvagno et al 1996;Stamler and Meissner 2001;Percival et al 2010, Figure 1). nNOSμ is scaffolded to the subsarcolemmal dystrophin glycoprotein complex (DGC) and neuromuscular junction (Brenman et al 1995(Brenman et al , 1996Adams et al 2000). The sarcolemmal nNOSμ association requires α-syntrophin, dystrophin, and α-dystrobrevin (Brenman et al 1995(Brenman et al , 1996Grady et al 2000;Adams et al 2000Adams et al , 2008.…”

Section: Introductionmentioning

confidence: 99%

“…nNOSμ is scaffolded to the subsarcolemmal dystrophin glycoprotein complex (DGC) and neuromuscular junction (Brenman et al 1995(Brenman et al , 1996Adams et al 2000). The sarcolemmal nNOSμ association requires α-syntrophin, dystrophin, and α-dystrobrevin (Brenman et al 1995(Brenman et al , 1996Grady et al 2000;Adams et al 2000Adams et al , 2008. In mice, nNOSμ is not only localized at the sarcolemma, but is also normally expressed at relatively high levels in the cytoplasm (Chang et al 1996;Kameya et al 1999;Thomas et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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nNOS regulation of skeletal muscle fatigue and exercise performance

Percival

2011

Biophys Rev

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Neuronal nitric oxide synthases (nNOS) are Ca 2+ /calmodulin-activated enzymes that synthesize the gaseous messenger nitric oxide (NO). nNOSμ and the recently described nNOSβ, both spliced nNOS isoforms, are important enzymatic sources of NO in skeletal muscle, a tissue long considered to be a paradigmatic system for studying NO-dependent redox signaling. nNOS is indispensable for skeletal muscle integrity and contractile performance, and deregulation of nNOSμ signaling is a common pathogenic feature of many neuromuscular diseases. Recent evidence suggests that both nNOSμ and nNOSβ regulate skeletal muscle size, strength, and fatigue resistance, making them important players in exercise performance. nNOSμ acts as an activity sensor and appears to assist skeletal muscle adaptation to new functional demands, particularly those of endurance exercise. Prolonged inactivity leads to nNOS-mediated muscle atrophy through a FoxO-dependent pathway. nNOS also plays a role in modulating exercise performance in neuromuscular disease. In the mdx mouse model of Duchenne muscular dystrophy, defective nNOS signaling is thought to restrict contractile capacity of working muscle in two ways: loss of sarcolemmal nNOSμ causes excessive ischemic damage while residual cytosolic nNOSμ contributes to hypernitrosylation of the ryanodine receptor, causing pathogenic Ca 2+ leak. This defect in Ca 2+ handling promotes muscle damage, weakness, and fatigue. This review addresses these recent advances in the understanding of nNOS-dependent redox regulation of skeletal muscle function and exercise performance under physiological and neuromuscular disease conditions.

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Absence of α-Syntrophin Leads to Structurally Aberrant Neuromuscular Synapses Deficient in Utrophin

Cited by 212 publications

References 59 publications

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

Biglycan regulates the expression and sarcolemmal localization of dystrobrevin, syntrophin, and nNOS

nNOS regulation of skeletal muscle fatigue and exercise performance

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