Ca2+-dependent and -independent activities of neural and non-neural synaptotagmins

Abstract

Synaptotagmins (Syts) are brain-specific Ca2+/phospholipid-binding proteins. In hippocampal synapses, Syt I is essential for fast Ca(2+)-dependent synaptic vesicle exocytosis but not for Ca(2+)-independent exocytosis. In vertebrates and invertebrates, Syt may therefore participate in Ca(2+)-dependent synaptic membrane fusion, either by serving as the Ca2+ sensor in the last step of fast Ca(2+)-triggered neurotransmitter release, or by collaborating with an additional Ca2+ sensor. While Syt I binds Ca2+ (refs 10, 11), its phospholipid binding is triggered at lower calcium concentrations (EC50 = 3-6 microM) than those required for exocytosis. Furthermore, Syts bind clathrin-AP2 with high affinity, indicating that they may play a general role in endocytosis rather than being confined to a specialized function in regulated exocytosis. Here we resolve this apparent contradiction by describing four Syts, three of which (Syt VI, VII and VIII) are widely expressed in non-neural tissues. All Syts tested share a common domain structure, with a cytoplasmic region composed of two C2 domains that interacts with clathrin-AP2 (Kd = 0.1-1.0 nM) and with neural and non-neural syntaxins. The first C2 domains of Syt I, II, III, V and VII, but not of IV, VI or VIII, bind phospholipids with a similar Ca(2+)-concentration dependence (EC50 = 3-6 microM). The same C2 domains also bind syntaxin as a function of Ca2+ but the Ca(2+)-concentration dependence of Syt I, II and V (> 200 microM) differs from that of Syt III and VII (< 10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

“…Synaptotagmin was up-regulated by cytokines in RINm5F cells, in agreement with a recent microarray analysis in INS-1 cells [12]. Synaptotagmin is an integral vesicle membrane protein generally associated with exocytosis and usually referred to as a calcium sensor [52,53,54]. However, several lines of evidence suggest that synaptotagmin might also be essential for endocytosis.…”

Widespread expression of human cysteine string proteins

“…Again, this is exemplified by reference to synaptotagmin. Li and colleagues [18] recently reported four new synaptotagmin isoforms that are distinct variants of the four previously identified forms of this protein.…”

Adrenal chromaffin cells contain functionally different SNAP‐25 monomers and SNAP‐25/syntaxin heterodimers

“…First, synaptobrevin and SNAP-25/syntaxin heterodimers present in the same vesicle may have an inappropriate orientation for the formation of a heterotrimer as opposed to synaptobrevin in a docked vesicle facing plasmalemmal syntaxin and SNAP-25. Second, protein-protein (or protein-lipid) interactions, for example binding of synaptotagmin [42,43], complexins [44] or secl homologues [4547] to syntaxin, may prevent the formation of the heterotrimers in the vesicular membrane. Specifically, n-secl inhibits the interaction of other proteins with syntaxin, including synaptobrevin and SNAP-25 [5].…”