Synaptic strength regulated by palmitate cycling on PSD-95.
Dynamic regulation of AMPA-type glutamate receptors represents a primary mechanism for controlling synaptic strength, though mechanisms for this process are poorly understood. The palmitoylated postsynaptic density protein, PSD-95, regulates synaptic plasticity and associates with the AMPA receptor trafficking protein, stargazin. Here, we identify palmitate cycling on PSD-95 at the synapse and find that palmitate turnover on PSD-95 is regulated by glutamate receptor activity. Acutely blocking palmitoylation disperses synaptic clusters of PSD-95 and causes a selective loss of synaptic AMPA receptors. We also find that rapid glutamate-mediated AMPA receptor internalization requires depalmitoylation of PSD-95. In a nonneuronal model system, clustering of PSD-95, stargazin, and AMPA receptors is also regulated by ongoing palmitoylation of PSD-95 at the plasma membrane. These studies suggest that palmitate cycling on PSD-95 can regulate synaptic strength and regulates aspects of activity-dependent plasticity.
El-Husseini
Alaa El-Din
Ael-D
Department of Physiology, University of California, San Francisco, CA 94143, USA.
Schnell
Eric
E
Dakoji
Srikanth
S
Sweeney
Neal
N
Zhou
Qiang
Q
Prange
Oliver
O
Gauthier-Campbell
Catherine
C
Aguilera-Moreno
Andrea
A
Nicoll
Roger A
RA
Bredt
David S
DS
D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000076122:Disks Large Homolog 4 Protein; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000166:cytology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007202:Indicators and Reagents / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000235:genetics; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010168:Palmitates / Q000378:metabolism* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
C491911:Cacng2 protein, rat; D015220:Calcium Channels; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D007004:Hypoglycemic Agents; D007202:Indicators and Reagents; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010168:Palmitates; D018091:Receptors, AMPA; C033652:postsynaptic density proteins; D049452:Green Fluorescent Proteins; C022776:2-bromopalmitate