In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 44 ( 2014-10-29), p. 14752-14768
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 Ca 2+ or by the E373K mutation that abolishes Ca 2+ -binding. Indeed, the ATP binding to SynI also occurred under Ca 2+ -free conditions and increased its association with purified rat SVs regardless of the presence of Ca 2+ and promoted SynI oligomerization. However, although under Ca 2+ -free conditions, SynI dimerization and SV clustering were enhanced, Ca 2+ favored the formation of tetramers at the expense of dimers and did not affect SV clustering, indicating a role of Ca 2+ -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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.1093-14.2014
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2014
detail.hit.zdb_id:
1475274-8
SSG:
12
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