Abstract
AP-1/σ1B-deficiency causes X-linked intellectual disability. AP-1/σ1B −/− mice have impaired synaptic vesicle recycling, fewer synaptic vesicles and enhanced endosome maturation mediated by AP-1/σ1A. Despite defects in synaptic vesicle recycling synapses contain two times more endocytic AP-2 clathrin-coated vesicles. We demonstrate increased formation of two classes of AP-2/clathrin coated vesicles. One which uncoats readily and a second with a stabilised clathrin coat. Coat stabilisation is mediated by three molecular mechanisms: reduced recruitment of Hsc70 and synaptojanin1 and enhanced μ2/AP-2 phosphorylation and activation. Stabilised AP-2 vesicles are enriched in the structural active zone proteins Git1 and stonin2 and synapses contain more Git1. Endocytosis of the synaptic vesicle exocytosis regulating Munc13 isoforms are differentially effected. Regulation of synaptic protein endocytosis by the differential stability of AP-2/clathrin coats is a novel molecular mechanism of synaptic plasticity.
Highlights
AP-2 clathrin-mediated-endocytosis (CME) facilitates SV endocytosis, AP-1 complexes mediate TGN/endosome protein sorting via clathrin-coated-vesicles (CCV)
There was no difference in the fractionation of AP-2 isolated from wt and σ1B −/− synapses on the gradient
The majority of AP-2 CCV in σ1B −/− synapses undergo rapid uncoating similar to wt CCV and the increase in AP-2 CCV could be solely due to enhanced CME, despite the reduction in SV recycling
Summary
AP-2 clathrin-mediated-endocytosis (CME) facilitates SV endocytosis, AP-1 complexes mediate TGN/endosome protein sorting via clathrin-coated-vesicles (CCV). AP-1/σ1B knock-out synapses show alterations in AP-1 dependent SV protein sorting and transport, and in CME1,2 They have slower and incomplete SV recycling, while early endosomes become enlarged. The changes in AP-1 and AP-2 dependent protein transport in σ1B −/− synapses are synapse specific and are novel molecular mechanisms of synaptic plasticity. Slower protein transport to acceptor organelles, e.g. early endosomes, would slow down recycling of SV proteins or of other synaptic plasma membrane proteins (receptors, ion channels, transporters) It would delay signal transduction pathways of internalised receptors. The novel AP-2 CCV are stabilised by three different molecular mechanisms, demonstrating complex regulatory mechanisms They are enriched in structural synaptic active zone (AZ) proteins and have a function in AZ plasticity. They reveal that AP-2/clathrin mediated endocytosis fulfils functions beyond the simple removal of proteins from the cell surface
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