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- Title
Functional Role of ATP Binding to Synapsin I In Synaptic Vesicle Trafficking and Release Dynamics.
- Authors
Orlando, Marta; Lignani, Gabriele; Maragliano, Luca; Fassio, Anna; Onofri, Franco; Baldelli, Pietro; Giovedí, Silvia; Benfenati, Fabio
- Abstract
Synapsins (Syns) are synaptic vesicle (SV)-associated proteins involved in the regulation of synaptic transmission and plasticity, which display a highly conserved ATP binding site in the central C-domain, whose functional role is unknown. Using molecular dynamics simulations, we demonstrated that ATP binding to SynI is mediated by a conformational transition of a flexible loop that opens to make the binding site accessible; such transition, prevented in the K269Q mutant, is not significantly affected in the absence of Ca2+ or by the E373K mutation that abolishes Ca2+-binding. Indeed, the ATP binding to SynI also occurred under Ca2+-free conditions and increased its association with purified rat SVs regardless of the presence of Ca2+and promoted SynI oligomerization. However, although under Ca2+-free conditions, SynI dimerization andSVclustering were enhanced, Ca2+favored the formation of tetramers at the expense of dimers and did not affect SV clustering, indicating a role of Ca2+-dependent dimer/tetramer transitions in the regulation of ATP-dependent SV clustering. To elucidate the role of ATP/SynI binding in synaptic physiology, mouse SynI knock-out hippocampal neurons were transduced with either wild-type or K269Q mutant SynI and inhibitory transmission was studied by patch-clamp and electron microscopy. K269Q-SynI expressing inhibitory synapses showed increased synaptic strength due to an increase in the release probability, an increased vulnerability to synaptic depression and a dysregulation of SV trafficking, when compared with wild-type SynI-expressing terminals. The results suggest that the ATP-SynI binding plays predocking and postdocking roles in the modulation of SV clustering and plasticity of inhibitory synapses.
- Subjects
ATP-binding cassette transporters; SYNAPSINS; SYNAPTIC vesicles; MOLECULAR dynamics; CONFORMATIONAL analysis
- Publication
Journal of Neuroscience, 2014, Vol 34, Issue 44, p14752
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1093-14.2014