Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia.
The switch from short-term to long-term facilitation of the synapses between sensory and motor neurons mediating gill and tail withdrawal reflexes in Aplysia requires CREB-mediated transcription and new protein synthesis. We isolated several downstream genes, one of which encodes a neuron-specific ubiquitin C-terminal hydrolase. This rapidly induced gene encodes an enzyme that associates with the proteasome and increases its proteolytic activity. This regulated proteolysis is essential for long-term facilitation. Inhibiting the expression or function of the hydrolase blocks induction of long-term but not short-term facilitation. We suggest that the enhanced proteasome activity increases degradation of substrates that normally inhibit long-term facilitation. Thus, through induction of the hydrolase and the resulting up-regulation of the ubiquitin pathway, learning recruits a regulated form of proteolysis that removes inhibitory constraints on long-term memory storage.
Hegde
A N
AN
Center for Neurobiology and Behavior, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
Inokuchi
K
K
Pei
W
W
Casadio
A
A
Ghirardi
M
M
Chain
D G
DG
Martin
K C
KC
Kandel
E R
ER
Schwartz
J H
JH
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001048:Aplysia / Q000502:physiology*; D001483:Base Sequence; D015152:Blotting, Northern; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017952:Ganglia, Invertebrate / Q000166:cytology; D017781:Genes, Immediate-Early / Q000502:physiology*; D017774:Long-Term Potentiation / Q000235:genetics*; D008568:Memory / Q000502:physiology; D008845:Microinjections; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012701:Serotonin / Q000494:pharmacology; D013379:Substrate Specificity; D013869:Thiolester Hydrolases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins / Q000378:metabolism
D000906:Antibodies; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D012333:RNA, Messenger; D014452:Ubiquitins; D012701:Serotonin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase