Gene/Protein
Disease
Symptom
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Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: EC:2.7.11.17 (
CaMKII
)
4,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Fast inhibitory synaptic transmission is predominantly mediated by GABA(A) receptor (GABA(A)R) in the CNS. Although several types of neuronal activity-dependent plasticity at GABAergic synapses have been reported, the detailed mechanism is elusive. Here we show that binding of structurally altered GABA(A)R-associated protein (
GABARAP
) to GABA(A)R gamma2 subunit and to tubulin is critical for long-term potentiation [called rebound potentiation (RP)] at inhibitory synapses on a cerebellar Purkinje neuron (PN). Either inhibition of
GABARAP
association with GABA(A)Rgamma2 or deletion of tubulin binding region of
GABARAP
impaired RP. Inhibition of tubulin polymerization also suppressed RP. Thus, precise regulation of GABA(A)Rgamma2-
GABARAP
-microtubule interaction is critical for RP. Furthermore, competitive inhibition of
GABARAP
binding to GABA(A)Rgamma2 after the RP establishment attenuated the potentiated response, suggesting that
GABARAP
is critical not only for the induction but also for the maintenance of RP. Fluorescence resonance energy transfer analysis revealed that
GABARAP
underwent sustained structural alteration after brief depolarization of a PN depending on the activity of
Ca2+/calmodulin-dependent protein kinase II
(CaMKII), which is required for the RP induction. The susceptibility of
GABARAP
to undergo structural alteration was abolished by an amino acid replacement in
GABARAP
. Furthermore, RP was impaired by expression of the mutant
GABARAP
with the replacement. Together, we conclude that GABA(A)R association with structurally altered
GABARAP
downstream of CaMKII activation is essential for RP.
...
PMID:Sustained structural change of GABA(A) receptor-associated protein underlies long-term potentiation at inhibitory synapses on a cerebellar Purkinje neuron. 1758 66
GABAergic dysfunction underlies many neurodevelopmental and psychiatric disorders. GABAergic synapses exhibit several forms of plasticity at both pre- and postsynaptic levels. NMDA receptor (NMDAR)-dependent inhibitory long-term potentiation (iLTP) at GABAergic postsynapses requires an increase in surface GABA
A
Rs through promoted exocytosis; however, the regulatory mechanisms and the neuropathological significance remain unclear. Here we report that the autism-related protein PX-RICS is involved in GABA
A
R transport driven during NMDAR-dependent GABAergic iLTP. Chemically induced iLTP elicited a rapid increase in surface GABA
A
Rs in wild-type mouse hippocampal neurons, but not in PX-RICS/RICS-deficient neurons. This increase in surface GABA
A
Rs required the PX-RICS/
GABARAP
/14-3-3 complex, as revealed by gene knockdown and rescue studies. iLTP induced
CaMKII
-dependent phosphorylation of PX-RICS to promote PX-RICS-14-3-3 assembly. Notably, PX-RICS/RICS-deficient mice showed impaired amygdala-dependent fear learning, which was ameliorated by potentiating GABAergic activity with clonazepam. Our results suggest that PX-RICS-mediated GABA
A
R trafficking is a key target for GABAergic plasticity and its dysfunction leads to atypical emotional processing underlying autism.
...
PMID:The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice. 3004 17
