Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 24, Pages 6431-6444Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0419-16.2016
Keywords
ABHD17; ABHD protein; AMPA receptor; palmitoylation; PSD-95; synapse
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology [15H04279, 15H01299, 26291045, 15H01570, 16H01371, 16K14560]
- Ministry of Health, Labour, and Welfare (Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP) [H27-7]
- Takeda Science Foundation
- Uehara Memorial Foundation
- Ono Medical Research Foundation
- Naito Foundation
- Daiichi Sankyo Foundation
- Grants-in-Aid for Scientific Research [15H01299, 15H04279, 16K14560, 26291045, 16H01371, 15H01570] Funding Source: KAKEN
Ask authors/readers for more resources
Postsynaptic density (PSD)-95, the most abundant postsynaptic scaffolding protein, plays a pivotal role in synapse development and function. Continuous palmitoylation cycles on PSD-95 are essential for its synaptic clustering and regulation of AMPA receptor function. However, molecular mechanisms for palmitate cycling on PSD-95 remain incompletely understood, as PSD-95 depalmitoylating enzymes remain unknown. Here, we isolated 38 mouse or rat serine hydrolases and found that a subset specifically depalmitoylated PSD-95 in heterologous cells. These enzymes showed distinct substrate specificity. alpha/beta-Hydrolase domain-containing protein 17 members (ABHD17A, 17B, and 17C), showing the strongest depalmitoylating activity to PSD-95, showed different localization from other candidates in rat hippocampal neurons, and were distributed to recycling endosomes, the dendritic plasma membrane, and the synaptic fraction. Expression of ABHD17 in neurons selectively reduced PSD-95 palmitoylation and synaptic clustering of PSD-95 and AMPA receptors. Furthermore, taking advantage of the acyl-PEGyl exchange gel shift (APEGS) method, we quantitatively monitored the palmitoylation stoichiometry and the depalmitoylation kinetics of representative synaptic proteins, PSD-95, GluA1, GluN2A, mGluR5, G alpha(q), and HRas. Unexpectedly, palmitate on all of them did not turn over in neurons. Uniquely, most of the PSD-95 population underwent rapid palmitoylation cycles, and palmitate cycling on PSD-95 decelerated accompanied by its increased stoichiometry as synapses developed, probably contributing to postsynaptic receptor consolidation. Finally, inhibition of ABHD17 expression dramatically delayed the kinetics of PSD-95 depalmitoylation. This study suggests that local palmitoylation machinery composed of synaptic DHHC palmitoylating enzymes and ABHD17 finely controls the amount of synaptic PSD-95 and synaptic function.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available