Functional role of ATP binding to synapsin I in synaptic vesicle trafficking and release dynamics.
J Neurosci
; 34(44): 14752-68, 2014 Oct 29.
Article
em En
| MEDLINE
| ID: mdl-25355227
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sinapses
/
Vesículas Sinápticas
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Trifosfato de Adenosina
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Sinapsinas
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Exocitose
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Neurônios
Limite:
Animals
Idioma:
En
Revista:
J Neurosci
Ano de publicação:
2014
Tipo de documento:
Article