Synaptic vesicle reuse

Ertunc M, Sara Y, Chung C, Atasoy D, Virmani T, Kavalali ET (2007) Fast synaptic vesicle reuse slows the rate of synaptic depression in the CA1 region of hippocampus. J Neurosci 27 341-54 Fonnum F, Fykse EM, Roseth S (1998) Uptake of glutamate into synaptic vesicles. Prog Brain Res 116 87-101... 

However, an alternative pathway that bypasses clathrin-mediated endocytosis and EEs appears to be available as well. This model of endocytosis known as kiss and run or its variant kiss and stay have attracted increasing interest in recent years [74] (Fig. 9-9B). Kiss and run has been directly demonstrated with dense-core granules in neuroendocrine cells [84, 85], and this model would explain some observations that are not readily accommodated by the classical pathway. The kiss and run model proposes that neurotransmitters are released by a transient fusion pore, rather than by a complete fusion with integration of the synaptic vesicle components into the plasma membrane. Synaptic membrane proteins never lose their association and the vesicle reforms when the pore closes. As a result, the empty vesicle can be refilled and reused without going through clathrin-mediated endocytosis and sorting in the EEs. 

Acetylcholine is synthesized from acetyl-CoA and choline in the cytoplasm of the presynap-tic axon [1] and is stored in synaptic vesicles, each of which contains around 1000-10 000 ACh molecules. After it is released by exocy-tosis (see p. 228), the transmitter travels by diffusion to the receptors on the postsynaptic membrane. Catalyzed by acetylcholinesterase, hydrolysis of ACh to acetate and choline immediately starts in the synaptic cleft [2], and within a few milliseconds, the ACh released has been eliminated again. The cleavage products choline and acetate are taken up again by the presynaptic neuron and reused for acetylcholine synthesis [3j. 

A synaptic vesicle cycle. The number of synaptic vesicles in a single synapse in the brain varies from fewer than 100 to several hundred. In specialized synapses there may be thousands. However, at any moment only a fraction of the total are in the "active zone," often aligned along the presynaptic membrane (Fig. 30-20A) or in specialized ribbons such as those in Fig. 30-10B. The vesicles are normally reused repeatedly, undergoing a cycle of filling with neurotransmitter, translocation to the active zone, ATP-dependent priming, exocytosis with release of the neurotransmitter into the synaptic cleft, coating with clathrin, endocytosis, and acidification as outlined in Fig. 30-20B.554-557 The entire cycle may be completed within 40-60 s to avoid depletion of active vesicles.558 559 A key event in the cycle is the arrival of an action potential at the presynaptic neuron end. 

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.

Synaptic vesicles are formed primarily by endocytic budding from the plasma membrane of axon terminals. Endocytosis usually involves clathrin-coated pits and is quite specific, in that several membrane proteins unique to the synaptic vesicles (e.g., neurotransmitter transporters) are specifically incorporated into the endocytosed vesicles. In this way, synaptic-vesicle membrane proteins can be reused and the recycled vesicles refilled with neurotransmitter (see Figure 17-36). 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

Glutamate is the primary excitatory neurotransmitter in the brain. Glutamate is formed by the Krebs cycle and is found free and stored in vesicles in synaptic terminals. Its release is calcium dependent, and an uptake system exists in presynaptic terminals and in glia to terminate its action after release. It is possible that glia metabolize glutamate to glutamine and return it to the neuron for reuse. An excessive release of glutamate can be lethal to cells in the immediate vicinity. 

---