While this may reflect a rather nonspecific effect of abnormalities of the postsynaptic cytoskeleton on the incidence of folds, it may also be that cycles of muscle fiber degeneration and regeneration, which are present in but not mice, there is a parallel reduction in the abundance of many of the proteins of the DPC (Ervasti et al., 1990; Ohlendieck and Campbell, 1991; Sewry et al., 1994). not essential for AChR clustering at the NMJ but may act as a component of the postsynaptic cytoskeleton, contributing to the development or maintenance of the postsynaptic folds. Defects of utrophin could underlie some forms of congenital myasthenic syndrome in which a reduction of postsynaptic folds is observed. Utrophin is a component of the membrane cytoskeleton, found in many tissues. It is a close homologue of dystrophin (reviewed in Blake et al., 1996), which causes the severe muscle wasting disease in man, Duchenne muscular dystrophy (Hoffman et al., 1987; Koenig et al., 1988). Both proteins are thought to link the internal cytoskeleton of the muscle cell to the extracellular matrix (reviewed in Ahn and Kunkel, 1993; Tinsley et al., 1994; Rabbit Polyclonal to FLI1 Campbell et al., 1995). The NH2-terminal region of dystrophin binds F-actin while the COOH-terminal region binds to -dystroglycan, a component of the dystrophin protein complex (DPC)1 (Ervasti et al., 1990; Ervasti and Campbell, 1991; Ibraghimov-Beskrovnaya, 1992). -Dystroglycan, a further component of the DPC, is thought to bind to laminin in the extracellular matrix (Ohlendieck and Campbell, 1991; Dickson et al., 1992; Ervasti and Campbell, 1993). Utrophin shares 85% amino acid conservation with dystrophin in the NH2- and COOH-terminal regions (Love et al., 1989; Tinsley et al., 1992) and is likely to have similar binding partners (Matsumura et al., 1992; Winder et al., 1995; Winder and Kendrick-Jones, 1995; James et al., 1996). Unlike dystrophin, which is only expressed in muscle and brain in the adult, utrophin is expressed in a wide variety of adult tissues. The presence of utrophin in vascular smooth muscle and the endothelium appears to underlie its very general tissue distribution with highest levels of protein and mRNA expression in lung and kidney (Love et al., 1989, 1991; Schofield et al., 1993). Utrophin appears early in the development of the mouse with the first transcripts detectable in the neural groove at embryonic day 8.5 (Schofield et al., 1993). Subsequent utrophin expression is particularly abundant in a subset of tissues derived from the neural crest such as peripheral nerve where it colocalizes with dystroglycan and homologues of other dystrophin-associated proteins (Matsumura et al., 1993). In many tissues and cultured cells, utrophin is present at specialized cellCcell or cellCextracellular matrix contacts. These include the foot processes of the kidney filtration barrier, the bronchial wall of the alveoli, and the intercalated discs of the heart (Pons et al., 1994) Fenoprofen calcium as well as focal adhesions and adherens-type junctions (Belkin et al., 1994; Belkin and Burridge, 1995). In brain, Fenoprofen calcium in addition to its enrichment in vascularized regions and in the astrocyte foot processes of the blood-brain barrier (Khurana et al., 1992), utrophin is reported to be present in the postsynaptic region of some synapses (Kamakura et al., 1994). In adult skeletal muscle fibers, in contrast to dystrophin, utrophin is present only at the neuromuscular junction (NMJ) and the myotendinous junction (Ohlendieck et al., 1991; Nguyen thi Man et al., 1991; Bewick et al., 1992), although a more general distribution is found in embryonic and regenerating muscle (Khurana et al., 1991; Helliwell et al., 1992; Karpati et al., 1993; Koga et al., 1993; Sewry et al., 1994). The NMJ is a cellCcell junction where utrophin is normally associated with an essential ligand-gated ion channel, the acetylcholine receptor (AChR). The postsynaptic membrane of the NMJ is characterized by extensive folding. Utrophin precisely colocalizes with the AChRs at the crests and upper part of these folds, while dystrophin and -spectrin are concentrated with voltage-gated sodium channels in the depths of the folds (Flucher and Daniels, 1989; Bewick et al., 1992; Sealock et al., 1991). This colocalization of utrophin and AChRs Fenoprofen calcium is present in the embryo from the earliest stage of AChR clustering and throughout the postnatal maturation of the NMJ (Phillips et al., 1993; Bewick et al., 1996) as is rapsyn, a NMJ-specific protein known to be essential Fenoprofen calcium in AChR clustering (Froehner et al., 1990; Phillips et al., 1991; Gautam et al., 1995). In contrast, spectrin and dystrophin do not appear at the NMJ.
Potassium Channels, Non-selective