Synaptotagmin IV regulates glial glutamate release

Abstract

Calcium-binding synaptotagmins (Syts) are membrane proteins that are conserved from nematode to human. Fifteen Syts (Syts I-XV) have been identified in mammalian species. Syt I has been well studied and is a candidate for the Ca 2؉ -sensor that triggers evoked exocytosis underlying fast synaptic transmission. Whereas the functions of the other Syts are unclear, Syt IV is of particular interest because it is rapidly up-regulated after chronic depolarization or seizures, and because null mutations exhibit deficits in fine motor coordination and hippocampus-dependent memory. Screening Syts I-XIII, which are enriched in brain, we find that Syt IV is located in processes of astroglia in situ. Reduction of Syt IV in astrocytes by RNA interference decreases Ca 2؉ -dependent glutamate release, a gliotransmission pathway that regulates synaptic transmission. Mutants of the C2B domain, the only putative Ca 2؉ -binding domain in Syt IV, act in a dominant-negative fashion over Ca 2؉ -regulated glial glutamate release, but not gliotransmission induced by changes in osmolarity. Because we find that Syt IV is expressed predominantly by astrocytes and is not in the presynaptic terminals of the hippocampus, and because Syt IV knockout mice exhibit hippocampal-based memory deficits, our data raise the intriguing possibility that Syt IV-mediated gliotransmission contributes to hippocampal-based memory.

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

“…46,47 Despite the lack of Ca 2+ binding by the Syt IV and Syt XI C2A domains, 46 Syt IV facilitates regulated exocytosis in neurons, astrocytes and endocrine cells. 28,[48][49][50] Similarly, Syt XI-containing vesicles undergo depolarization-triggered exocytosis in neurons. 42 Similar to neuronal lysosomes, 51 Syt XI-containing exocytic vesicles in neurons are acidic in nature and localize to dendrites.…”

“…28 Whereas all these synaptotagmins showed punctate expression, only Syt XI colocalized with lysosomes (Figures 4a and b). Syt XI is the most abundant Syt isoform in astrocytes and is expressed more abundantly in the astrocytes as compared with the neurons; 27,28,30 however, its subcellular localization in astrocytes is not known. 41,42 Use of western blot analysis confirmed expression of Syt XI protein in primary astrocytes (Figure 4c).…”

“…Synaptotagmin VII is known to regulate lysosomal exocytosis; 29,38 however, Syt VII expression in astrocytes is disputed. 27,28 Multiple Syt VII isoforms reported in neurons and chromaffin cells. 39,40 Mouse myoblasts expressed two Syt VII isoforms (45 and 51 kDa), whereas mouse astrocytes showed very weak expression of the 51-kDa and none of the 45-kDa isoform (Figure 3a).…”

Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

“…SYT IV, SYT VII and REST silencing vectors Specific small interfering RNA (siRNA) were designed as follows: for rat Syt4, the sense target sequence 5′GAAGCACAAAGT GAAAACCA3′ was deduced from the reported mouse sequence [18]; for rat Syt7 the sense sequence 5′TCAT CACCGTCAGCCTTAG3′ was selected according to a previous publication [19]; for REST, the sense sequence 5′ GGAACCTGTTGAGAAGGGA3′ was selected using the siRNA Target Finder (Ambion, Austin, TX, USA). Two complementary DNA fragments encoding the target sequence and separated from the reverse complement by a short spacer were synthesised by Microsynth (Balgach, Switzerland).…”

Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity

“…They generated a transgenic mouse with astrocytic over-expression of a dominant-negative form of synaptobrevin-2, which largely abrogates exocytotic release selectively from astrocytes (Zhang et al, 2004). They found that this lead to the disappearance of the tonic A 1 receptor-mediated inhibition on synaptic transmission in hippocampal slices (Pascual et al, 2005).…”