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KCND2 binds DPP6. 52 / 53
2 | 2 48
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"We show that activity-induced Kv4.2 phosphorylation triggers Pin1 binding to, and isomerization of, Kv4.2 at the pThr 607 -Pro motif, leading to the dissociation of the Kv4.2-DPP6 complex."
32218435
sparser
"CA1 pyramidal neurons of the hippocampus from these mice exhibited altered Kv4.2-DPP6 interaction, increased A-type K + current, and reduced neuronal excitability."
32218435
sparser
"Thus, the regulation of the Kv4.2-DPP6 complex may not only affect Kv4.2 channel activity but also influence Kv4.2-independent functions of DPP6."
32218435
sparser
"In the present study, we report a Pin1-dependent mechanism that regulates the composition of the Kv4.2-DPP6 complex, neuronal excitability and cognitive flexibility."
32218435
sparser
"Our previous studies showed that a p38-Pin1-Kv4.2 pathway regulates the Kv4.2-DPP6 complex. xref We hypothesized that activity-dependent degradation of Kv4.2 by UBE3A occurs on DPP6 containing Kv4.2 complexes."
40310720
sparser
"Using biochemical and electrophysiological techniques, we showed that Pin1 activity is required for the dissociation of the Kv4.2-DPP6 complex and this action alters neuronal excitability."
32218435
sparser
"However, Pin1C113S induces a higher degree of reduction of UBE3A-Kv4.2 association when co-expressed with Kv4.2-DPP6 complexes compared to expression with Kv4.2-KChIP2 complexes ( xref ), suggesting that Kv4.2 phosphorylation and Pin1 isomerization increases UBE3A binding to Kv4.2."
40310720
biogrid
No evidence text available
15454437
sparser
"P38-Pin1-Kv4.2 pathway regulates Kv4.2-DPP6 complex formation."
32218435
sparser
"We wondered if the Kv4.2-DPP6 complex is regulated by Kv4.2 phosphorylation and Pin1 activity."
32218435
sparser
"Experiments mutating the N-terminal, however, show that the intracellular portion is necessary for the interaction between DPP6 and Kv4.2 [ xref , xref ]."
36012450
sparser
"Indeed, in the context of the regulation of DPP6-Kv4.2 dynamics, p38 activity in the apical dendrites may be of particular significance."
32824677
sparser
"Using co-immunoprecipitation, they identified the short intracellular N-terminal domain (32 aa at the N-terminus) plus the transmembrane domain (total 54 aa) as important in facilitating DPP6-Kv4.2 interaction, while the extracellular C-terminal domain is required for trafficking out of the ER and membrane expression of Kv4.2 [ xref ]."
36012450
sparser
"We have reported previously, using a heterologous expression system, that the intracellular N-terminal and transmembrane regions of DPP6 associate with Kv4.2 and accelerate channel kinetics."
29651237
sparser
"Similar signal transduction was found by Kv4.2 that phosphorylated Kv4.2 enhanced ERK phosphorylation ( Schrader et al., 2009 ), and the auxiliary structural units of Kv4.2, KCHIP and DPP6 complexes i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34384853
sparser
"The result showed that expression of DPP6 or KChIP2 decreased Kv4.2 phosphorylation at T602 and T607, but all complexes including Kv4.2 alone, Kv4.2-DPP6, Kv4.2-KChIP2, and Kv4.2-DPP6-KChIP2 are capable of being phosphorylated by p38 ( xref )."
40310720
sparser
"As PTZ-induced seizure enhanced Kv4.2 phosphorylation at T607 by p38 (Figs.  xref xref ), we sought to determine if this seizure model also alters Kv4.2-DPP6 binding."
32218435
sparser
"From co-IP, we found that PTZ-induced seizure reduced Kv4.2-DPP6 binding in the mouse brain (Fig.  xref )."
32218435
sparser
"Previous work demonstrated that DPPX tightly binds to Kv4.2, but not Kv3.1, proteins ()."
15911355
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"Furthermore, the PTZ-induced Kv4.2-DPP6 complex dissociation was blocked by the Pin1 inhibitor Juglone (Fig.  xref )."
32218435
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"This Kv4.2-DPP6 complex dissociation was blocked by the p38 inhibitor SB203580, but not the MEK inhibitor SL327 (Fig.  xref ), suggesting that p38 is required for the dissociation of the Kv4.2-DPP6 complex."
32218435
sparser
"In cultured mouse neurons, synaptic stimulation with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 50 µM) for 15 min resulted in decreased Kv4.2-DPP6 binding, which was opposed by the expression of PinC113S, an isomerase dead mutant (Fig.  xref )."
32218435
sparser
"These data suggest that Pin1 activity is required for the dissociation of the Kv4.2-DPP6 complex in response to neuronal activity."
32218435
sparser
"We next examined if the regulation of Kv4.2-DPP6 binding is altered in Kv4.2TA mice."
32218435
sparser
"However, Kv4.2-DPP6 dissociation by PTZ-induced seizure was abolished in Kv4.2TA mice (Fig.  xref )."
32218435
sparser
"This data supports the notion that both Kv4.2 phosphorylation at T607 and Pin1 activity regulate Kv4.2-DPP6 complex formation."
32218435
biogrid
No evidence text available
23692269
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"Our previous study defined a Pin1 isomerase-dependent mechanism that regulates the composition of the Kv4.2-DPP6 complex, neuronal excitability, and cognitive flexibility. xref In response to activity, Kv4.2 is phosphorylated at T607 by p38 kinase, which triggers Pin1 binding to and isomerization of Kv4.2, resulting in Kv4.2-DPP6 dissociation. xref Kv4.2 and DPP6 have been implicated in neurological diseases, such as autism spectrum disorder, xref – xref temporal lobe epilepsy, xref , xref fragile X syndrome, xref , xref and neurodegeneration. xref In the present study, we identify Kv4.2 as an activity-dependent substrate of UBE3A via a tandem affinity purification-mass spectrometry (TAP-MS) pull-down assay."
40310720
sparser
"The basal level of Kv4.2-DPP6 protein complex seems unaltered in Kv4.2TA mice compared to WT littermates in biochemistry experiments (Fig.  xref ) whereas we found reduced neuronal excitability in Kv4.2TA mice (Fig.  xref )."
32218435
sparser
"Since the Kv4.2-DPP6 complex is mis-regulated in Kv4.2TA mice (Fig.  xref ), we anticipated disruption of Pin1-Kv4.2 interaction would alter I A . To test this, we performed voltage-clamp recordings from outside-out patches pulled from CA1 pyramidal somata."
32218435
sparser
"The molecular complex of DPP6 and Kv4.2 likely includes other dipeptidyl aminopeptidase-like proteins such as DPP10, as well as K + channel interacting proteins (KChIPs) ( xref )."
36209950
sparser
"Future studies will determine if DPP10 is affected in the DPP6-KO; if it is a common associate in a complex with DPP6 and Kv4.2, then the loss of DPP6 could affect the levels of DPP10 and perhaps adversely affect the function of the potassium channel complexes and lead directly to some of the changes that we see in the DPP6-KO."
36209950
sparser
"The present study describes a Pin1 isomerase-dependent mechanism that regulates the composition of the Kv4.2-DPP6 complex, neuronal excitability, and cognitive flexibility (Fig.  xref )."
32218435
reach
"Normally Pin1 stabilizes the Kv4.2-DPP6 complex [73] and enhances NMDA-R function [74] both contributing to cognitive flexibility and plasticity."
37849016
sparser
"Importantly, we also found that p38-Pin1-Kv4.2 pathway regulates Kv4.2-DPP6 complex (Fig.  xref ) and neuronal excitability (Fig.  xref )."
32218435
sparser
"The mechanism how Pin1-elicited Kv4.2 conformation change leads to Kv4.2-DPP6 disassociation is interesting and needs to be elucidated in follow up studies."
32218435
sparser
"Our biochemistry data showed that Kv4.2-DPP6 dissociation is impaired in Kv4.2TA mice, indicating that the Kv4.2-DPP6 complex is more stable without phosphorylation at T607."
32218435
sparser
"The basal level of Kv4.2-DPP6 protein complex is not altered in Kv4.2TA mice compared to WT littermates in biochemistry experiments (Fig.  xref )."
32218435
sparser
"Taken together, our data demonstrate that Pin1 regulates the composition of the Kv4.2-DPP6 complex and neuronal excitability."
32218435
sparser
"Considering that both Kv4.2 and DPP6 are implicated in such psychiatric disorders xref , xref , xref , the stability of the Kv4.2-DPP6 complex might be a common factor of pathophysiology."
32218435
sparser
"Taken together, our results reveal that disrupting the activity-dependent isomerization of Kv4.2 by Pin1 stabilizes the Kv4.2-DPP6 complex and improves cognitive flexibility."
32218435
sparser
"Stabilization of the Kv4.2-DPP6 complex might represent a promising strategy for enhancing adaptive cognitive behavior and correcting maladaptive cognitive deficits in a number of neuropsychiatric conditions."
32218435
sparser
"DPP6 interacts with potassium channel Kv4.2 (KCND2), enhancing its membrane expression and channel kinetics."
40109277
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"Specifically, Kv4.2 and its association with DPP6 is key in regulating spike-timing-dependent long-term potentiation (STD LTP). xref We hypothesized that the dysregulation of Kv4.2-DPP6 complexes, increase in Kv4.2 protein levels, and Kv4.2-induced alterations in excitatory synaptic connectivity in SR of the hippocampus of AS mice may contribute to impairments in plasticity and learning and memory observed in the disease."
40310720
sparser
"KChIP4a, which negatively affects the impact of other KChIPs on Kv4.2, also inhibits the effects of DPPXS, consistent with the formation of a ternary complex of Kv4.2, DPPX-S and KChIPs early in channel biosynthesis."
19441798
reach
"Experiments mutating the N-terminal, however, show that the intracellular portion is necessary for the interaction between DPP6 and Kv4.2 [7,18]."
36012450
sparser
"Given DPP6′s role as an auxiliary subunit, Hu et al. investigated p38 and Pin1′s regulation of Kv4.2-DPP6 association."
36012450
sparser
"Similar blockade of Kv4.2-DPP6 dissociation was also shown to reduce kainic acid induced seizure intensity in mice [ xref ]."
36012450
sparser
"It is plausible that activity-dependent/dynamic regulation of DPP6-Kv4.2 association and turnover may impart synapse state-dependent changes, altering the expression and consolidation of synaptic plasticity in a bi-directional manner."
36012450
sparser
"Normally Pin1 stabilizes the Kv4.2-DPP6 complex [ xref ] and enhances NMDA-R function [ xref ] both contributing to cognitive flexibility and plasticity."
37849016
sparser
"Therefore, it appears that neuronal activity induces Kv4.2 phosphorylation at the Pin1 site on Kv4.2-DPP6 complexes, causes Pin1 isomerization of Kv4.2, dissociation from DPP6, and Kv4.2 internalization."
40310720
sparser
"The majority of studies to date focus on DPP6-Kv4.2 in hippocampal CA1 pyramidal neurons, but to fully appreciate DPP6 contributions to neural circuit function in normal and pathogenic states, the expression pattern of isoforms is required."
36012450