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Full Version: Vesicular Trafficking - A Major Pathway of Neurotransmission
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The cellular membrane structure is a stable protein-lipid bilayer; however, it is not static in nature. The transport and the movement of the secretory proteins as well as different factors occur continuously across the membrane. The unique feature of the membranes to fuse with other membranes without losing continuity and the continuous reorganization of the membranes within the eukaryotic endo-membrane system is responsible for many of the biological functions of the membranes like transport, secretion, etc.

The specific membrane fusion between two membranes requires:

i) The recognition between the two membranes

ii) Apposition of the membranes with the removal of water molecules associated with the lipid polar head group

iii) The disruption in the bilayer structures resulting in hemifusion, i.e. fusion of the outer leaflet of each membrane

iv) The formation of continuous bilayer with the fusion of the two bilayers.

The triggering of the fusion between the bilayers at the appropriate time or in response to a particular and specific signal is required for the process of receptor-mediated endocytosis or for regulated secretion of various factors or proteins. These events are mediated by integral proteins in the membranes or within the cells called fusion proteins, which bring about specific recognition and the formation of a local distortion transiently for favouring membrane fusion. The secretion of neurotransmitters into the synapse and the process of neurotransmission is one of the most widely studied cases of membrane fusion.

The lipids play a very essential role in the process of exocytosis, being the building blocks of the membrane structure, as the distortion in the bilayer arrangement of the lipid in the membranes helps in the merging of the membranes during the process of fusion. It is facilitated by the presence of non-cylindrical lipids like lysolipids, phosphatidic acid, fatty acids, etc. The cellular concentration of these lipids is low in resting stage and increases with the stimulation and secretion of different lipases. The fact that lysolipids play an important role in exocytosis is supported by their presence in high concentration in the vesicles of the neuroendocrine cells and in the stimulated exocytosis of the neurotransmitters with the Phospholipase A2 secretion. The machinery involving the zippering of the N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins has proved to be capable of mediating the membrane fusion in-vitro. Hence, the role of proteins is also very essential in the membrane fusion process.

The electric impulses travel across the axon of the neurons and the signals are transmitted to the next neuron or the target effectors or cells in the form of the neurotransmitters. These neurotransmitters are contained in the vesicles, which are present within the neurons. A Synapse is the junction between two neurons or between a neuron and its target cell and helps in the transmission of the signals through the synaptic cleft. In the resting stage, it is believed that the synaptic vesicles are loaded with neurotransmitters and they either remain free in the cytoplasm linked to the actin filaments with the help of synapsin bridges or remain docked in the pre-synaptic membrane. The main mechanism of the transmission occurs due to the depolarization of the pre-synaptic membrane leading to the opening of the voltage-gated Ca2+ channels, which triggers the entry of Ca2+ into the pre-synaptic membrane. This results in the fusion of the synaptic vesicles with the pre-synaptic membrane, thereby resulting in the release of the neurotransmitters into the synaptic cleft. These neurotransmitters then bind to the receptors on the post-synaptic membrane resulting in the opening of the ion-gated channels, which leads to the entry of Na+, K+, Ca2+, Cl- into the post-synaptic membrane, depending upon the selectivity of the ion channel. After the fusion and release of the neurotransmitters, the vesicle membranes are retrieved rapidly and are reutilized for the generation of further neurotransmitter-loaded vesicles. The ions, which enter through the opening of the voltage-gated channels or ion-gated channels are used for further cell signalling mechanism. This machinery of the exo-endocytic recycling coordination requires complex mechanisms integrating cell signal transduction, other dynamic changes within the membrane structure and rearrangements of the cytoskeletal elements within the cell.

Although, much research has been conducted regarding the study of the synaptic transmission through the vesicular traffic process, all the proteins involved in the exocytosis and endocytosis of the synaptic vesicles are not known yet. Recent evidence has suggested the role of Synaptotagmin, a phopholipid dependent Ca2+ binding protein involved in the exocytosis of the vesicles. However, the possible involvement of other proteins in the process is yet to be discovered. Proper understanding of the molecular mechanism of the fusion of the membranes of synaptic vesicles and pre-synaptic membrane can be achieved only through the identification and characterization of the different components of the fusion complex formed during the interaction of the synaptic vesicle with the pre-synaptic membrane.