Molecular Mechanism on the Block of Neurotransmitter Release with Inositol Polyphosphates

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We previously demonstrated that the C2B domain of synaptotagmin is an inositol polyphosphates (IPs) binding site, and synaptic transmission in squid giant synapse is completely blocked by injection of IPs into the presynaptic terminal. From these results, we suggested that synaptotagmin is a functional molecule directly involved in the neurotransmitter release, and is a target molecule of IPs in the block of synaptic transmission. In 1995, in order to verify this idea, we investigated whether specific antibody to the C2B domain (this antibody inhibits binding of IP4 to the C2B domain) is able to release the block of neurotransmission by IPs using squid giant synapse. The result revealed that the block of synaptic transmission is completely released with coinjection of IPs and the antibody. Moreover, with high frequent stimulation after injection of the antibody, synaptic response rapidly reduced, and drastical reduction of synaptic vesicle was observed. These results strongly suggest that synaptotagmin is a target molecule in the block of neurotransmission with IPs, and is involved in both phenomenons of exocytosis and endocytosis. In 1996, we performed a similar study in cell level using the primary culture from mammalian cells, rat superior cervical ganglion neurons (electrophysiological approarch) and bovine adrenal chromaffin cells (catecholamine release). The results demonstrated that the same phenomenons were observed on the blocking effect by IPs and release of block by coinjection with the C2B antibody. These results strongly suggest that IPs are ubiquitous modulator of synaptotagmin over the species.