Abstract
In an active nerve terminal, exocytosis and endocytosis proceed at a frenzied pace. Each action potential releases ≈0.5% of the total supply of synaptic vesicles in the terminal (1), and, with some neurons firing at a rate of 50 Hz or greater, synapses would lose the ability to secrete neurotransmitter within seconds if they could not reform and refill synaptic vesicles. Endocytosis is the principal means, and perhaps the only means, by which the used vesicles are recovered and recycled into the releasable vesicle pool (2). Moreover, the rate of endocytosis is tightly coupled to the rate of exocytosis. In a resting terminal, endocytosis rates are low, but activity can increase this rate enormously to preserve the balance of exocytosis and endocytosis and thereby preserve the sizes of the nerve terminal and vesicle pool. How the rate of endocytosis is regulated, however, remains obscure. In this issue of PNAS, Nicholson-Tomishima and Ryan (3) report that synaptotagmin I, one of the principal proteins of the synaptic vesicle, has an important role to play in promoting the efficient endocytosis of synaptic vesicles. Synaptotagmin I has already been established as a significant contributor to exocytosis of synaptic vesicles (4). This protein is thus of consequence to both sides of the vesicle cycle at nerve endings. (Fig. 1). Fig. 1. Synaptotagmin coming and going. Vesicles in the nerve terminal are recycled for repeated use. In promoting exocytosis, synaptotagmin interacts with membranes and the SNARE complex, the complex of syntaxin, SNAP-25, and synaptobrevin that likely mediate vesicle fusion. In promoting endocytosis, synaptotagmin interacts with the clathrin adaptor complex AP-2. Precisely because of its involvement in exocytosis, synaptotagmin's involvement in endocytosis has long been suspected but difficult to establish. If endocytosis is decreased in a nerve terminal lacking synaptotagmin, is this due to a direct role of …
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