Example research essay topic: Shown In Figure Neuromuscular Junction - 1,660 words

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Proteins involved in formation of the neuromuscular junction The neuromuscular junction is a specialized junction, where a motor nerve forms its synaptic terminal with a muscle fibre, one of many fibres that make up a whole muscle. The mature neuromuscular junction is composed of three types of cells - a motor nerve terminal, a muscle fibre and a Schwann cell covering the junction. All three of these cells are highly differentiated and specialized for their functions (Kandel 2000, p. 1089). The events that occur during the formation of the neuromuscular junction have been extensively studied and are the most comprehensively understood of any nerve-to-target cell contact.

Prior to formation of the synapse all three components of the neuromuscular junction develop and acquire identities independently. The muscle cells are derived from the mesoderm and migrate from the dermomyotomal portion of the somite. Motoneurons migrate from the ventricular zone of the neural tube to a ventral-lateral location before axons grow out of the spinal cord. Schwann cells are glial cells, which insulate the axons outside of the spinal cord, they are derived from neural crest cells and associate with axons from the somite onwards to the peripheral target.

At the time of the first axons reaching the developing muscle, the muscle fibres are my oblasts that have just fused to form multi nucleated myotube's, there is no evidence to suggest that motor neurons prefer certain site on the developing myo tube or that there is a predetermined site for the formation of the synapse, on the contrary, synapse formation can occur on most, if not all of the myo tube surface (Licht man et al in Zig mond et al 2000, pp. 547 - 8). Acetylcholine receptors (A ChR) are found uniformly dispersed over the surface of the myo tube until the nerve approaches the myo tube. As the nerve approaches the myo tube a protein known as again, which is synthesized in the motor neuron, is transported down the axon to the synaptic cleft where it is released from the nerve terminal, here it is deposited in the synaptic basal lamina. The major components of the basal lamina are laminin's, which are made up of &# 945; , &# 946; and &# 947; chains; it forms a continuous non-myelin layer over the nerve terminal and is a potent promoter of axon outgrowth. The basal lamina is present (at least components of the basal lamina are present) prior to the arrival of the nerve and is rich in the enzyme acetylcholinesterase (AChE), an enzyme which catalyses the breakdown of acetylcholine (ACh) the major neurotransmitter at the neuromuscular junction. Again acts through receptors in the plasma membrane of the muscle fibre, it brings about the localization of the A ChR to the region below the nerve terminal, the aggregation of A ChR is essential for the development of the neuromuscular junction.

Again also regulates the distribution of other synaptic proteins, such as AChE, raison, utrophin and neuregulin (NRG) receptors, this indicates again has a central role in synaptic differentiation. The again gene is expressed in a variety of cell types, for example again is also synthesized by muscle cells, however, the neuronal isoforms of again are a thousand times more active in the aggregation of A ChR. It has been shown that again is an essential component for A ChR clustering, by using antibodies against again; it was shown A ChR clustering is blocked and the neuromuscular junction cannot mature (Rest et al 1992, p. 867). The exact mechanism of again-mediated A ChR clustering is not yet known, but a receptor tyrosine kinase known as muscle-specific kinase or MuSK has been shown to be a vital component of the again receptor complex.

MuSK is normally found aggregated at the synaptic sites. However, again does not bind directly to MuSK, so the again receptor may contain an additional subunit. Exactly how again interacts with MuSK is not yet known. It has been shown however that MuSK is an essential component for A ChR clustering, as mice with the MuSK gene which has been genetically disrupted, lack normal neuromuscular junctions (Gautam et al 1996, p. 531) The steps that follow MuSK activation and that lead to postsynaptic differentiation are not yet known.

However, it seems likely that another molecule is involved in again-mediated signaling, a protein termed raison. Again stimulates clustering of raison in myotube's in cell culture, and clustering of raison and A ChR appears to occur coincidentally at synapse formation (Burden, S. J. 1985, p. 8272) Rapsyn has been shown to be critical for synapse formation, as mice lacking raison expression, die within a few hours after birth (Gautam et al 1995, p. 234) The clustering of A ChR at the post-synaptic site is maintained further via: 1) A mechanism of increased A ChR production by nuclei at the synaptic site due to the release of a nerve derived component, termed neuregulin (NRG) that acts via ErbB receptors on the muscle fibre, this is shown in figure 1 2) Reduction of A ChR production at nuclei in extra-synaptic locations, i. e. nuclei outside the synaptic site produce less A ChR. NRG is capable of stimulating expression of the genes for the acetylcholine receptor subunit, by stimulating transcription of the protein, via the ErbB receptors found in the postsynaptic membrane at neuromuscular synapses.

NRG is synthesized in the motor neurons as well as the muscle fibre, similar to again. Summary of the formation of the neuromuscular junction -The three cells types that comprise the mature neuromuscular junction all develop independently prior to the formation of the synapse. As the growth cone of the motor neuron approaches the developing muscle, the multi nucleated myo tube has just been formed by the fusion of the my oblasts and elements of the basal lamina are already present. -The terminal accumulates synaptic vesicles containing ACh the main neurotransmitter at the synapse. ACh receptors are uniformly spread over the myo tube prior to the arrival of the motor neuron, but as the motor neuron approaches it synthesizes and secretes the protein again into the synaptic cleft. -The again binds to the receptors on the muscle surface and initiates clustering of the A ChR to the synapse, an intracellular protein called raison appears to play a pivotal role in this process. A muscle specific tyrosine kinase (MuSK) is also essential in the clustering of A ChR, it is thought to be a part of the again receptor complex, although again does not bind directly to it -Both again and MuSK are essential for the normal development of the neuromuscular junction. -As the muscle matures, multiple axons form synapses with the one muscle fibre, however strong synaptic inputs influence the muscle to decrease intracellular components that are supporting synapses from axons that weakly influence the post-synaptic site, this is illustrated in figure 2. One hypothesis is that active synapses punish inactive neighbours by secreting molecules that have been termed synaptomedians. -As the neuromuscular junction matures the extra axons retreat and eventually only one motor neuron synapses with a fibre.

The motor neuron terminal is rich in vesicles containing ACh; many of these vesicles are clustered in dense patches on the presynaptic membrane called active zones. -The postsynaptic membrane on the muscle fibre has indents which lie directly opposite to these active sites, the indents are called junctional folds and are rich in A ChR. -An illustration of the mature neuromuscular junction is shown in figure 3. Disorders of the neuromuscular junction Myasthenia Gravis There are several disorders of the neuromuscular junction; one of these is myasthenia gravis (which means severe weakness of muscle). There are two major forms of myasthenia gravis; the first and most prevalent is the autoimmune form. The autoimmune form is one of few diseases that fulfill the strict criteria for an immune-mediated disease. Which are, (1) an antibody is present in almost all cases. (2) The antibody acts with an antigen that is important in the pathophysiology of the disease. (3) By transferring antibodies to experimental animals, features of the disease can be reproduced. (4) An experimental form of the illness can be induced, by immunizing animals with the antigen. (4) Therapeutic reduction of antibody levels relieves symptoms (Kandel et al 2000, p. 298). The second and less common form of myasthenia gravis is congenital and heritable; it is not autoimmune and is heterogeneous.

Firstly we will be concentrating on the more common autoimmune form of myasthenia gravis. In the autoimmune form, antibodies are produced against the nicotinic A ChR in the muscle. The A ChR antibodies appear to produce the neuromuscular transmission defect in MG by 1) binding to the A ChR and affecting its function, 2) accelerating the degradation rate of A ChR and thereby lowering the concentration of A ChR, and 3) causing complement-mediated lysis of the muscle end plate (Boonyapisit et al 1999, p. 102) The first mechanism appears to be relatively insignificant, but dramatic exceptions do exist that may be clinically important. Their effect appears to be a direct blockade of ACh-induced opening of the ion channel. In patients such antibodies appear to be only a small percentage of total A ChR antibodies, and their effect on the end plate potential is small. The antibodies can cross-link A ChR and increase their degradation rate; the reduction of A ChR concentration at the end plate is brought about in part by an increase in A ChR degradation By far the most significant effect of the A ChR antibody is complement-mediated destruction of the neuromuscular junction.

The geometry of the end-plate is also disturbed by this; the normal infolding at the junctional folds is reduced and the synaptic cleft is enlarged which leads to loss of A ChR-rich membrane (Yoga et al 2001, pp. 6 - 10). Alteration in the architecture of the junctional folds decreases the amount of membrane surface available for A ChR insertion, this is shown in figure 4. All thes...

Research essay sample on Shown In Figure Neuromuscular Junction