SV2 Renders Primed Synaptic Vesicles Competent for Ca²⁺-Induced Exocytosis

Abstract

Synaptic vesicle protein 2 (SV2), one of the first synaptic vesicle proteins identified, is characterized by multiple transmembrane regions that exhibit homology to sugar transporters, and by a highly glycosylated intravesicular sequence. Deletion of SV2 causes postnatal lethality in mice, primarily because of fulminant epilepsy. At the cellular level, deletion of SV2 impairs neurotransmitter release, but its function is unknown, and even the exact point at which release is affected in SV2-deleted synapses remains unclear. Using electrophysiological approaches, we now examine at what step in exocytosis the deletion of SV2 impairs release. Our data demonstrate that deletion of SV2 produces a decrease in evoked synaptic responses without causing changes in mini frequency, mini amplitude, the readily releasable pool of vesicles, or the apparent Ca 2ϩ sensitivity of vesicle fusion. These findings indicate that a previously unidentified step may couple priming of synaptic vesicles to Ca 2ϩ triggering of fusion, and that SV2 acts in this step to render primed synaptic vesicles fully Ca 2ϩ responsive. To investigate the structural requirements for this function of SV2, we used rescue experiments. We demonstrate that conserved charged residues within the transmembrane regions and the intravesicular glycosylation of SV2 are required for its normal folding and trafficking. In contrast, the conserved putative synaptotagmin-binding sequence of SV2 is fully dispensable. Viewed together, these observations suggest that SV2 functions in a maturation step of primed vesicles that converts the vesicles into a Ca 2ϩ -and synaptotagmin-responsive state.

The Presynaptic Active Zone Protein RIM1α Controls Epileptogenesis following Status Epilepticus

“…Like RIM1␣, SV2A has been implied to be involved in the molecular mechanisms underlying both priming-by rendering primed synaptic vesicles competent for Ca 2ϩ -induced exocytosis (Chang and Südhof, 2009) and by enhancing release probability at quiescent synapses (Custer et al, 2006)-and presynaptic ho-meostatic plasticity as a target of miR-485 (Cohen et al, 2011). Blocking of miR-485 in turn reverses the homeostatic reduction in synaptic connectivity after incubation of neuronal cultures for 5 d with BiC/4-AP.…”

Axonal Patterns and Targets of dA1 Interneurons in the Chick Hindbrain

“…Notably, GFP ϩ synapses that were not costained with the presynaptic markers synaptotagmin/ SV2 were also frequently detected. This finding may result from the former expression of SV2-GFP during the maturation steps of the presynaptic vesicle, compared with synaptotagmin, which is induced by SV2 and acts in the functional synapse at the cone termini (Chang and Südhof, 2009;Morgans et al, 2009;Yao et al, 2010;Bragina et al, 2011).…”

The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

“…Synaptotagmin is required for the calcium-mediated exocytosis of neurotransmitters stored in synaptic vesicles (5). SV2A also plays a synaptotagmin-independent role in neurotransmitter release, most likely functioning in a maturation step of primed synaptic vesicles that converts the vesicles into a Ca 2ϩ -and synaptotagmin-responsive state (6). The exact function of SV2A, however, still remains elusive.…”