Docking vesicle

Inactivation of the a-synuclein gene by homologous recombination results in mice that appear largely normal [3]. Analysis of mice lacking y-synuclein has similarly failed to reveal any gross abnormalities [4]. In hippocampal slices from mice without a-synuclein, the replenishment of docked vesicles by reserve pool vesicles was slower than in slices from control mice. It suggests a physiological role for a-synuclein in the mobilization of synaptic vesicles. 

In contrast, genetic deletion of RIMla in mice revealed that the protein is required for long-term potentiation both in the hippocampus and in the cerebellum. Biochemical experiments revealed that RIMla is part of a presynaptic protein scaffold containing active zone proteins that is required for normal release of neurotransmitters. No change in the number of docked vesicles was observed, however, suggesting that other proteins are needed for the docking of synaptic vesicles at active zones. 

Figure 1 Overview of the synaptic vesicle cycle, (a) Within the presynaptic terminal, synaptic vesicles are filled with neurotransmitter by the action of specific vesicular neurotransmitter transporters, (b) Neurotransmitter-filled vesicles translocate to the active-zone membrane where they undergo docking, (c) Docked vesicles transition to a release-competent state through a series of priming or prefusion reactions, (d) Invasion of an action potential into the presynaptic terminal and subsequent calcium influx induces rapid fusion of the synaptic vesicle membrane with the terminal membrane, which thereby releases the neurotransmitter into the synaptic cleft, (e) Spent vesicles are internalized by clathrin-mediated endocytosis and are recycled for reuse, which thus completes the synaptic vesicle cycle. SV, synaptic vesicle CCV, clathrin-coated vesicle EE, early endosome. NOTE The use of arrows indicates a temporal sequence of events. Physical translocation of synaptic vesicles is unlikely to occur between the docking and fusion steps.

Nofal S, Becherer U, Hof D, Matti U, Rettig J. Primed vesicles can be distinguished from docked vesicles by analyzing their mobility. J. Neurosci. 2007 27 1386-1395. 

A typical presynaptic bouton is a specialized portion of the axon. It is characterized by an active zone, a region where the presynaptic plasma membrane comes into close contact with the postsynaptic plasma membrane and an associated cluster of vesicles (De Camilli et al., 2001). A few synaptic vesicles are adjacent to the active zone and are referred to as docked vesicles. Vesicle exocytosis occurs at the active zone subsequent endocytic retrieval of vesicular components may occur both at the active zone and in the peri-active zone area (Roos and Kelly, 1999). Vesicle maturation involves acidification of the lumen, loading with the neurotransmitter, association with peripheral membrane proteins needed for exocytosis, and recapture into a vesicle cluster. The vesicle cluster is embedded in an ac tin-rich area and is generally located next to mitochondria, which provides the energy required for the vesicle cycle and neurotransmitter dynamics and to the endoplasmic reticulum whose function includes the regulation of local cytosolic calcium. 

Two pools of neurotransmitter-filled synaptic vesicles are present in axon terminals those docked at the plasma membrane, which can be readily exocytosed, and those in reserve in the active zone near the plasma membrane. Each rise in Ca triggers exocytosls of about 10 percent of the docked vesicles. Membrane proteins unique to synaptic vesicles then are specifically internalized by endocytosis, usually via the same types of clathrln-coated vesicles used to recover other plasma-membrane proteins by other types of cells. After the endocytosed vesicles lose their clathrln coat, they are rapidly refilled with neurotransmitter. The ability of many neurons to fire 50 times a second is clear evidence that the recycling of vesicle membrane proteins occurs quite rapidly. 

The exocytosis of neurotransmitters from synaptic vesicles Involves targeting and fusion events similar to those that lead to release of secreted proteins In the secretory pathway. However, several unique features permit the very rapid release of neurotransmitters In response to arrival of an action potential at the presynaptic axon terminal. For example. In resting neurons some neurotransmitter-fllled synaptic vesicles are docked at the plasma membrane others are In reserve In the active zone near the plasma membrane at the synaptic cleft. In addition, the membrane of synaptic vesicles contains a specialized Ca -blndlng protein that senses the rise In cytosolic Ca " after arrival of an action potential, triggering rapid fusion of docked vesicles with the presynaptic membrane. 

A EXPERIMENTAL FIGURE 17-35 Fibrous proteins help localize synaptic vesicles to the active zone of axon terminals. In this micrograph of an axon terminal obtained by the rapid-freezing deep-etch technique, synapsin fibers can be seen to interconnect the vesicles and to connect some to the active zone of the plasma membrane. Docked vesicles are ready to be exocytosed. Those toward the center of the terminal are in the process of being filled with neurotransmitter. [From D. M. D. Landis et al., 1988, Neuron 1 201.]... 

B. In response to a nerve impulse (action potential), voltagegated Ca channels in the plasma membrane open, allowing an influx of Ca from the extracellular medium. The resulting Ca -induced conformational change in synaptotagmin leads to fusion of docked vesicles with the plasma membrane and release of neurotransmitters into the synaptic cleft. Step B After... 

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