Synaptotagmin and neurotransmitter release

Abstract

William M. DeBello,’ Heinrich Bet Torri-Tarelli et al., 1985), and that this exocytosis is trig- gered by a rise in the concentration of Ca within presynap- tic terminals (Miledi, 1973). The source of this triggering Ca is the voltage-gated Ca channel, which is found in close proximity to the sites of exocytosis (Augustine et al., 1987). Ca is thought to trigger exocytosis by binding to a Ca- selective receptor protein within the presynaptic terminal (Silinsky, 1985); the identity of this protein and its molecu- lar modus operandi have thus far eluded detection. Synaptotagmin, a Presynaptic Ca-Binding Protein One interesting candidate for this Ca receptor is synapto- tagmin, an integral membrane protein of synapticvesicles. Although synaptotagmin was discovered more than ten years ago (Matthew et al., 1981), interest in this protein languished until its primary sequence was deduced from the cloning and sequencing of its gene (Perrin et al., 1990; Wendland et al., 1991). The discovery of two repeats of an amino acid motif, called the C2 domain, that is thought to confer Ca- and lipid-binding properties to a large family of related proteins (Perrin et al., 1990; Clark et al., 1991) rekindled interest in synaptotagmin. Recent studies have shown that synaptotagmin does indeed bind Ca and that Ca binding increases synaptotagmin’s ability to bind lipids (Brose et al., 1992). Such properties conceivably could allow synaptotagmin to not only sense changes in the pre- synaptic Ca concentration but also to mediate vesicle- plasma membrane fusion (Brose et al., 1992). Close scrutiny of synaptotagmin’s properties revealed that a number of these attributes appear to be shared by the hypothetical Ca receptor that triggers transmitter release (Table 1). First, transmitter secretion is known to require local rises in intracellular Ca concentration on the order of hundreds of PM (Augustine et al., 1991; Llinas et al., 1992), and synaptotagmin binds Ca in this concentra- tion range (arose et al., 1992). Second, the physiological observation of a fourth-order relationship between Ca entry and transmitter secretion (Dodge and Rahamimoff, 1967; Augustine and Charlton, 1986) is paralleled in the fourth-order Ca binding properties of synaptotagmin (Brose