The Expression And Function Of Dystrophin Glycoprotein Complex In Neuronal Cholinergic Synapses

Synapses are areas of contact between cells which are highly specialized for transmission of chemical signals. To maximize sensitivity during signaling, neurotransmitter receptors and other proteins involved in signal transduction are concentrated precisely beneath the site of neurotransmitter release. The synaptic cytoskeleton like PSD is thought to immobilize to the signal transduction apparatus and hence maintain and modulate the structure of the synapses. Dystrophin is a large cytoskeletal protein originally identified as the gene product mutated in Duchenne and Becker muscular dystrophies. Subsequent biochemical and molecular studies have shown that dystrophin is a major component of a large muscle membrane-associated complex, the dystrophin glycoprotein complex (DGC). The DGC consists of the cytoskeletal-associated dystrophin; two groups of cytoplasmic proteins, the dystrobrevins and syntrophins; and three groups of transmembrane proteins, dystroglycans, sarcoglycans and sarcospan. The DGC plays a critical role in maintaining muscle stability by linking the actin cytoskeleton to the extracellular matrix. Dystrophin directly binds to actin at one end and to the intracellular domain of the transmembrane protein p-dystroglycan at the other end. The extracellular domain of P-dystroglycan binds to a-dystroglycan, which in turn binds to extracellular matrix protein agrin and Iaminina2 in the basal lamina. Furthermore, dystrophin also binds to syntrophins and a-dystrobrevin, two classes of proteins involved in signal transduction. The importance of this complex in maintaining muscle stability is clearly demonstrated by the findings that mutations in dystrophin and any of the foursarcoglycan genes lead to muscular dystrophies in human. Furthermore, mice lacking dystroglycans, α-dystrobrevin or α-syntrophin all show various degrees of muscular dystrophy.There are two characterization in DGC. One is the components of the DGC are encoded by multiple related genes are subject to alternative splicing. For example, in addition to dystrophin which is itself subject to extensive alternative splicing; there exists the structurally analogous utrophin. The dystrophin family also includes dystrobrevin with its various splicing isoforms, and the closely related protein p-dystrobrevin, similarly, three different syntrophin genes have been identified, at least two of which are subject to alternative.The another characterization in DGC is the various isoforms of the dystrophin complex show differential tissue express. Interestingly, it appears that some isoforms are synapses specific. For example, many of the DGC proteins are express in neurons of the central and peripheral nervous system. There include dystrophin, utrophin, dystroglycans, dystrobrevins and syntrophins. Therefore, it has been speculated that the DGC may play a similar role at neuron-neuron synapses as it does at the NMJ. Currently, however, there is little direct evidence that the DGC is important for the formation and/or maintenance of neuron-neuron synapses.Recent studies have indicated that a-dystrobrevin may also regulate the clustering and/or stability of nAChRs at the postsynaptic membrane of the NMJ. a-dystrobrevin is a key component of the dystrophin glycoprotein complex (DGC). It was originally identified by its co-purification with nAChRs from Torpeto californica electric organ, suggesting a tight association with nAChRs. a-dystrobrevin directly binds to the C-terminal of dystrophin and utrophin to form a complex with other DGC proteins, a-dystrobrevin deficient mice show muscular dystrophy and instability of the NMJ despite that the DGC structure is largely intact, suggesting that a-dystrobrevin plays a signaling rather than a structural role in the muscle and at the NMJ. Furthermore, a-dystrobrevin binds syntrophin which in turn binds other signaling molecules, such as nitric oxide synthase, further enhance the signaling capability of a-dystrobrevin.Currently, molecular mechanisms regulating the targeting and anchoring of neuronal...