Synaptic vesicle recycling

Bauerfeind, R., Galli, T. and DeCamilli, P. Molecular mechanisms in synaptic vesicle recycling. /. Neurocytol. 25 701-716, 1996. 

In a simplistic model, the exocytosis step of neurotransmission takes place in at least three major different steps 158 Many years have passed since the concept of synaptic vesicle recycling was introduced in the early 1970s, but details of the synaptic vesicle cycle continue to be a matter for investigation and debate 160... 

The bulk of pinocytosis in the nervous system is mediated by clathrin-mediated endocytosis (CME) [55] and this is the best-characterized pathway. More detail about clathrin-mediated pathways will be given when receptor-mediated endocytosis and the synaptic vesicle cycle pathways are considered. Pinocytosis through CME is responsible for uptake of essential nutrients such as cholesterol bound to low density lipoprotein (LDL) and transferring, but also plays a role in regulating the levels of membrane pumps and channels in neurons. Finally, CME is critical for normal synaptic vesicle recycling. 

N-ethylmaleimide-sensitive Trimeric ATPase required for in vitro membrane fusion during vesicular transport. Probably function as factor (NSF) chaperones in synaptic vesicle recycling. 

Many years have passed since the concept of synaptic vesicle recycling was introduced in the early 1970s, but... 

In the classic model of synaptic vesicle recycling in nerve terminals, synaptic vesicles fuse completely with the plasma membrane and the integrated vesicle proteins move away from the active zone to adjacent membrane regions (Fig. 9-9A). In these regions, clathrin-mediated synaptic vesicle endocytosis takes place rapidly after neurotransmitter release (within seconds) [64]. The process starts with the formation of a clathrin-coated pit that invaginates toward the interior of the cell and pinches off to form a clathrin-coated vesicle [83]. Coated vesicles are transient organelles that rapidly shed their coats in an ATP/chaperone dependent process. Once uncoated, the recycled vesicle fuses with a local EE for reconstitution as a synaptic vesicle. Subsequently, the recycled synaptic vesicle is filled with neurotransmitter and it returns to the release site ready for use. This may be the normal pathway when neurotransmitter release rates are modest. Clathrin/ EE-based pathways become essential when synaptic proteins have been incorporated into the presynaptic plasma membrane. 

Morris, S. A. and Schmid, S. L. Synaptic vesicle recycling. The Ferrari of endocytosis Curr. Biol. 5 113-115,1995. 

Multiple physiological roles for IP6 and the diphosphoinositol polyphosphates have been proposed, including effects on endocytosis and mRNA transport [3] however, definitive evidence for many of these functions is lacking. Such studies are complicated by possible nonspecific effects of this highly negatively charged molecule. Of note is the report of an IP6/IP7-dependent protein kinase activity that phosphorylates pacsin/syndapin I, a protein involved in synaptic vesicle recycling [21]. 

Studying Synaptic Vesicle Recycling Using Electrophysiological Techniques-- 28... 

Betz WJ, Bewick GS (1992) Optical analysis of synaptic vesicle recycling at the frog neuromuscular junction. Science 255 200-3... 

Betz WJ, Bewick GS (1993) Optical monitoring of transmitter release and synaptic vesicle recycling at the frog neuromuscular junction. J Physiol 460 287-309 Betz WJ, Mao F, Smith CB (1996) Imaging exocytosis and endocytosis. Curr Opin Neurobiol 6 365-71... 

Virmani T, Han W, Liu X, Sudhof TC, Kavalali ET (2003) Synaptotagmin 7 splice variants differentially regulate synaptic vesicle recycling. EMBO J 22 5347-57 Voglmaier SM, Kam K, Yang H, Fortin DL, Hua Z, Nicoll RA, Edwards RH (2006) Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling. Neuron 51 71-84... 

Rizzoli SO, Richards DA, Betz WJ (2003) Monitoring synaptic vesicle recycling in frog motor nerve terminals with FM dyes. J Neurocytol 32 539-549. 

Presently, it cannot be excluded that despite the apparently highly specific function of certain Rabs in intracellular trafficking pathways there is redundancy with respect to vesicle docking in the synapse. The surprising diversity of Rabs on highly purified synaptic vesicles (more than 30 different Rabs) supports the view that multiple Rabs are required for synaptic vesicle recycling, which may have overlapping functions. 

Fig. 5 Synaptic vesicle recycling in the synapse. For synaptic vesicle recycling, several endocytic mechanisms appear to co-exist in synaptic nerve terminals. In the case of fast kiss-and-ran exo-cytosis/endocytosis, the fused vesicle does not collapse into the membrane but is retrieved directly by a fast process. The molecular machinery underlying this pathway is unknown. Vesicles that have fully collapsed into the membrane are recycled by clathrin-mediated endocytosis. Clathrin, along with other proteins, is involved in membrane invagination (see figure and text) and leads finally to the formation of a constricted pit. The GTPase dynamin (black ring) mediates membrane scission of the constricted pit. After removal of the clathrin coat, two pathways are possible (direct recycling and recycling via the early endosome). In all cases, before fusion the recycled vesicles have to be loaded with neurotransmitters (NT).

Conklin BR, Farfel Z, Lustig KD et al (1993) Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha. Nature 363 274-6 Cousin MA, Robinson PJ (2000) Two mechanisms of synaptic vesicle recycling in rat brain nerve terminals. J Neurochem 75 1645-53... 

Wang C, Zucker RS (1998) Regulation of synaptic vesicle recycling by calcium and serotonin. Neuron 21 155-67... 

Verderio, C., Rossetto, O., Grumelli, C., Frassoni, C., Montecucco, C., Matteoli, M. (2006). Entering neurons botulinum toxins and synaptic vesicle recycling. EMBO Rep. 7 995-9. 

The concept of synaptic vesicle recycling was conclusively established in the early 1970s (Holtzman et al., 1971 Cec-carelli et al., 1973 Heuser and Reese, 1973), and the role of clathrin-mediated endocytosis in the recycling of synaptic vesicles is now well established. A model of endocytosis referred to as kiss-and-run has attracted considerable interest (Ceccarelli et al., 1973 Fesce et al., 1994). In this model, vesicles release neurotransmitter via a transient fusion pore. Newly reformed vesicles may then stay in place, be reloaded, and undergo a new round of exocytosis or may de-dock and allow other vesicles to take their place. 

Thymoquinone. Thymoquinone (TQ) is the main constituent of the oil extracted from Nigella sativa seeds, with antioxidant and anti-inflammatory effects. Treatment with TQ efficiently attenuates APi 2-induced neurotoxicity, inhibits the mitochondrial membrane potential depolarization and ROS generation caused by Api 2, restores synaptic vesicle recycling inhibition, partially reverses the loss of spontaneous firing activity, and inhibits A(f aggregation in vitro [291],... 

VijayRaghavan K (1995) Synaptic vesicle recycling intermediates revealed. Bioessays 17 195-198... 

Cousin MA, Nicholls DG (1997) Synaptic vesicle recycling in cultured cerebellar granule cells role of vesicular acidification and refilling. J Neurochem 69 1927-1935. 

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