Disease relevance of Snta1

• Alpha1-syntrophin-deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration [1].
• The anchoring of AQP4 to alpha-syntrophin may be a target for treatment of brain edema, but therapeutic manipulations of AQP4 must consider the bidirectional water flux through this molecule [2].
• Surprisingly, AQP4 was strongly reduced but alpha-syntrophin was retained in perivascular astroglial end-feet in WT mice examined 23 h after transient cerebral ischemia [2].
• Furthermore, we have demonstrated for the first time that DeltaC microdystrophin can eliminate interstitial fibrosis and macrophage infiltration and restore dystrobrevin and syntrophin to the dystrophin-associated glycoprotein complex [3].
• These in vivo mouse studies highlight the functional importance of appropriate membrane targeting of nNOS by the dystrophin-associated protein alpha-syntrophin and may have implications for the development of potential gene therapy strategies to treat muscular dystrophy or other muscle-related diseases [4].

High impact information on Snta1

• However, nNOS does not associate with alpha 1-syntrophin on the sarcolemma in transgenic mdx mice expressing truncated dystrophin proteins [5].
• An NH2-terminal domain of nNOS directly interacts with alpha 1-syntrophin but not with other proteins in the dystrophin complex analyzed [5].
• These patterns of expression suggest that syntrophin-1 and syntrophin-2 may associate with different members of the dystrophin family [6].
• Two forms of mouse syntrophin, a 58 kd dystrophin-associated protein, differ in primary structure and tissue distribution [6].
• Syntrophin-1 mRNA (2.2 kb) is expressed at highest levels in skeletal muscle [6].

Biological context of Snta1

• The mouse alpha 1-syntrophin gene ( > 24 kilobases) is comprised of eight exons [7].
• The alpha 1-syntrophin gene is located on human chromosome 20 and mouse chromosome 2, while the beta 2-syntrophin gene is on human chromosome 16 and mouse chromosome 8 [7].
• Primer extension analysis reveals two transcription initiation sites in the alpha 1-syntrophin gene and a single site in the beta 2-syntrophin gene [7].
• Binding of laminin alpha1-chain LG4-5 domain to alpha-dystroglycan causes tyrosine phosphorylation of syntrophin to initiate Rac1 signaling [8].
• Altogether, our findings suggest that ARMS may play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EphA4 [9].

Anatomical context of Snta1

• Syntrophin, a 58 kd extrinsic membrane protein, is concentrated at postsynaptic sites at the neuromuscular junction and may be involved in clustering acetylcholine receptors [6].
• alpha-Syntrophin is a scaffolding adapter protein expressed primarily on the sarcolemma of skeletal muscle [10].
• Expression of the alpha1-syntrophin is predominant in CA regions and the olfactory bulb and it is also present in the cerebral cortex and the dentate gyrus [11].
• Finally, no syntrophin was detected in the cerebellar Purkinje cells where the specific dystrophin isoform (P-type) is present [11].
• Syntrophin expression co-localizes with utrophin in the choroid plexus and caudate putamen [11].

Associations of Snta1 with chemical compounds

• Co-expression of alpha1-syntrophin significantly increased the apoA-I-mediated release of cholesterol [12].
• In the presence of E3 or laminin-1, syntrophin is phosphorylated on a tyrosine residue, and this increases and alters Grb2 binding [8].
• Syntrophin A (residues 4-274) is predominantly a dimer in EGTA [13].
• Pleckstrin homology domain 1 of mouse alpha 1-syntrophin binds phosphatidylinositol 4,5-bisphosphate [14].
• Neuronal type nitric oxide synthase-mu is enriched in fast-twitch fibers and binds to syntrophin, a component of the sarcolemmal dystrophin glycoprotein complex [15].

Physical interactions of Snta1

• Grb2-binding to syntrophin is increased by the addition of either laminin-1 or the isolated laminin alpha1 globular domain modules LG4-5, a protein referred to as E3 [8].
• Mouse alpha1 syntrophin binds the COOH-terminal domain of dystrophin, and calmodulin inhibits this interaction in a Ca2+-dependent fashion [13].
• Where calmodulin binds to syntrophin was investigated by constructing fusion proteins containing different regions of syntrophin's sequence [13].
• In vitro immunoprecipitation and pull-down assays demonstrated that Kir4.1 can bind directly to alpha-syntrophin, requiring the presence of the last three amino acids of the channel (SNV), a consensus PDZ domain-binding motif [16].

Regulatory relationships of Snta1

• Moreover, the ephrin-A1-induced tyrosine phosphorylation of EphA4 was reduced in C2C12 myotubes after the blockade of ARMS and alpha-syntrophin expression by RNA interference [9].
• Syntrophin was also able to inhibit actin-activated myosin ATPase activity and actomyosin super-precipitation. alpha-Syntrophin co-localized with cortical F-actin fibers when expressed in Chinese hamster ovary cells, and deletion of the actin-binding region abolished co-localization [17].

Other interactions of Snta1

• AQP4 expression has been reported to be absent at the sarcolemma and the perivascular astrocyte endfoot processes of alpha1-syntrophin knockout mice [18].
• Fusion proteins containing alpha-syntrophin sequences bound not only to dystrophin but also to all three DGC syntrophins, adhalin, and gp35 [19].
• Differential effect of alpha-syntrophin knockout on aquaporin-4 and Kir4.1 expression in retinal macroglial cells in mice [20].
• The amino-terminal 174 residue section of syntrophin contains other calmodulin binding, and binding occurs in either the presence or absence of Ca2+ with an apparent affinity of 100 nM [13].
• Previously, a signaling pathway was described [Oak, Zhou, and Jarrett (2003) J. Biol. Chem. 278, 39287-39295] that links matrix laminin binding on the outside of the sarcolemma to Grb2 binding to syntrophin on the inside surface of the sarcolemma and by way of Grb2-Sos1-Rac1-PAK1-JNK ultimately results in the phosphorylation of c-jun on Ser(65) [8].

Analytical, diagnostic and therapeutic context of Snta1

• Genetic crosses with the mdx mouse showed that neither transgenic syntrophin could associate with the sarcolemma in the absence of dystrophin [10].
• To test this hypothesis, we investigated the ultrasturctural localization of AQP4 and alpha1-syntrophin in the brain astrocytes by using double immunogold labeled electron microscopy [18].
• Immunoprecipitation revealed that alpha1-syntrophin interacted with ABCA1 strongly and that the interaction was via the C-terminal three amino acids SYV of ABCA1 [12].
• A selective removal of perivascular AQP4 by alpha-syntrophin deletion delays the buildup of brain edema (assessed by Diffusion-weighted MRI) following water intoxication, despite the presence of a normal complement of endothelial AQP4 [21].
• Somatic cell hybrids and fluorescent in situ hybridization were both used to determine their chromosomal locations: beta 2-syntrophin to chromosome 16q22-23 and alpha 1-syntrophin to chromosome 20q11 [22].

References