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CALM binds KCNQ2. 86 / 87
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"Disruption of calmodulin binding to KCNQ2 also impairs enrichment of heteromeric KCNQ2/KCNQ3 channels at the axonal surface by blocking their trafficking from the endoplasmic reticulum to the axon."
25077630
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"To test whether CaM interaction with KCNQ2 regulates the targeting of CD4-Q2C to the axonal surface, we introduced point mutations in helix A of KCNQ2 including two BFNC mutations, L339R and R353G xref ( xref )."
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"The second group found that both wt CaM and DN CaM interact with KCNQ2, consistent with our results that DN CaM can act as a dominant negative in CaM actions."
12810850
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"The interaction of the Kv7.2 C-terminus with CaM was used as positive control."
17482572
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"Two recent studies have determined the structures of Kv7.2-CaM complexes."
30022004
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"CaM was able to bind KCNQ2(C527R) protein in the calcium (–) condition ( xref )."
24349250
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"Using immunocytochemistry and the cluster of differentiation 4 (CD4) membrane protein as a trafficking reporter, we demonstrate that fusion of KCNQ2 carboxy-terminal tail is sufficient to target CD4 protein to the axonal surface whereas inhibition of calmodulin binding to KCNQ2 abolishes axonal surface expression of CD4 fusion proteins by retaining them in the endoplasmic reticulum."
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"Considering the modest effect of CaM1234 on the axonal surface expression of HA-KCNQ3 and KCNQ2 channels (XREF_FIG), CaM bound to KCNQ2 may act as a Ca 2+ sensor for modulating not only the M-current, but also the channel density at the axonal membrane."
25077630
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"The Interaction between KCNQ2 Channels and Calmodulin is Regulated by CK2-Mediated Phosphorylation of the Lobe Linker."
32075037
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"This review aims to summarize the functional findings together with the different mechanisms of action proposed for the interaction of CaM with Kv7.2 channels."
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"After the KCNQ2 and CaM complex was purified by immunoprecipitation in calcium (-) condition, dissociation of CaM from KCNQ2 protein was examined by exposing KCNQ2-CaM resin to calcium (XREF_FIG)."
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"The R353G mutation located distal to the IQ motif ( xref ) has been shown to moderately reduce CaM binding to KCNQ2 in HEK293T cells xref , xref ."
25077630
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"These results support the hypothesis that changes in calcium levels alter KCNQ2-CaM binding, which leads to the suppression of the current."
24349250
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"Since the KCNQ2(R353G) channel with impaired CaM binding and low PIP2 affinity xref showed a stronger response to ionomycin, it would be reasonable to assume that the KCNQ2-CaM interaction regulates PIP2 affinity of the KCNQ2 subunit as we reported previously xref ."
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"In contrast, the A343D mutation, which blocked CaM binding to KCNQ2 (XREF_FIG) XREF_BIBR, XREF_BIBR, abolished surface and intracellular expression of HA-KCNQ3 and KCNQ2 channels at the AIS and distal axons (XREF_FIG, XREF_FIG) and reduced the surface " Axon and Dendrite " ratio to below 1 (XREF_FIG)."
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"In addition, Ca 2 + / CaM binds the 1-5-10 motifs of both KCNQ2 and KCNQ3 with a low-affinity, and favours subunit interaction."
24333508
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"Disruption of CaM binding to KCNQ2 impairs trafficking of HA-KCNQ3 and KCNQ2 channels from the ER to the axon."
25077630
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"To test whether CaM interaction with KCNQ2 regulates the targeting of CD4-Q2C to the axonal surface, we introduced point mutations in helix A of KCNQ2 including two BFNC mutations, L339R and R353G XREF_BIBR (XREF_FIG)."
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"Mutations in the Kv7.2 CaM binding domain interfere with the PIP activation of the channel [57], suggesting that CaM might compete with PIP [58]."
30022004
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"Since the R353G mutation in KCNQ2 reduces CaM binding to heteromeric KCNQ2 and KCNQ3 channels only by 20% XREF_BIBR, XREF_BIBR, our results suggest that a greater degree of impairment in CaM binding to KCNQ2 is needed to prevent targeting of heteromeric channels to the axonal surface."
25077630
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"It has been proposed that Ca 2+ does not influence the association of CaM with Kv7.2/7.3 heteromers [ xref ], or that the interaction of Kv7.2 with CaM is weaker [ xref ] or stronger in the absence of Ca 2+ [ xref , xref , xref , xref , xref , xref ]."
30022004
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"Disruption of calmodulin binding to KCNQ2 also impairs enrichment of heteromeric KCNQ2 and KCNQ3 channels at the axonal surface by blocking their trafficking from the endoplasmic reticulum to the axon."
25077630
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"Although CaM can still interact with KCNQ3 subunits xref , xref , the A343D mutation, which abolished CaM binding to KCNQ2 ( xref ), prevented surface and intracellular expression of intact HA-KCNQ3/KCNQ2 channels at the AIS and distal axons ( xref – xref ), consistent with a recent study reporting altered neuronal distribution of heteromeric channels by the I340A mutation xref ."
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"In contrast, the BFNC R353G mutation located distal to the IQ motif modestly reduced but did not abolish CaM binding to KCNQ2 (XREF_FIG) and had minimal effect on the polarized axonal surface expression of HA-KCNQ3 and KCNQ2 channels (XREF_FIG)."
25077630
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"KCNQ2 subunit associates with another CaM binding protein as a constituent of the channel complex: AKAP79/150, a scaffold protein critical for KCNQ2 channel regulation xref , xref ."
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"The R353G mutation located distal to the IQ motif (XREF_FIG) has been shown to moderately reduce CaM binding to KCNQ2 in HEK293T cells XREF_BIBR, XREF_BIBR."
25077630
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"The first CaM-binding motif has a sequence that conforms partially to the consensus IQ motif, but both wild-type CaM and a Ca2+-insensitive CaM mutant bind to KCNQ2."
12223552
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"The first CaM binding motif has a sequence that conforms partially to the consensus IQ motif, but both wild-type CaM and a Ca2 +-insensitive CaM mutant bind to KCNQ2."
12223552
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"Moreover, binding of WT CaM to KCNQ2 can moderately reduce the constitutive current through KCNQ2 homomeric channels by changing channel structure."
23630338
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"Using immunocytochemistry and the cluster of differentiation 4 (CD4) membrane protein as a trafficking reporter, we demonstrate that fusion of KCNQ2 carboxy-terminal tail is sufficient to target CD4 protein to the axonal surface whereas inhibition of calmodulin binding to KCNQ2 abolishes axonal surface expression of CD4 fusion proteins by retaining them in the endoplasmic reticulum."
25077630
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"Calmodulin bound to the KCNQ2 subunit regulates channel trafficking and stabilizes channel activity."
24627475
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"Although CaM can still interact with KCNQ3 subunits XREF_BIBR, XREF_BIBR, the A343D mutation, which abolished CaM binding to KCNQ2 (XREF_FIG), prevented surface and intracellular expression of intact HA-KCNQ3 and KCNQ2 channels at the AIS and distal axons (XREF_FIG - XREF_FIG), consistent with a recent study reporting altered neuronal distribution of heteromeric channels by the I340A mutation XREF_BIBR."
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"These results together suggest that disruption of CaM binding to KCNQ2 impairs the trafficking of CD4-Q2C proteins from the ER to the AIS and distal axons."
25077630
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"However, in contrast to the wild-type KCNQ2 subunit, addition of 100 µM calcium further increased binding of CaM to KCNQ2(C527R) ( xref )."
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"These data are entirely consistent with the concept that CaM bound to KCNQ2 acts as a Ca2+ sensor, conferring Ca2+ dependence to the trafficking of the channel to the plasma membrane and fully explaining the requirement of CaM binding for KCNQ2 function."
19494108
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"Since CaM interaction with KCNQ2 is required for functional expression of KCNQ channels in non neuronal cells XREF_BIBR, XREF_BIBR, XREF_BIBR, we hypothesized that CaM regulates preferential targeting of KCNQ channels to the axonal surface."
25077630
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"Here we show that the L339R mutation in helix A, which is linked to human benign neonatal convulsions, perturbs CaM binding to KCNQ2 channels and prevents their correct trafficking to the plasma membrane."
19494108
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"These results together indicate that disruption of CaM interaction with KCNQ2 by the A343D mutation impairs the trafficking of HA-KCNQ3/KCNQ2 channels from the ER to the axon."
25077630
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"As suggested by secondary structure prediction, the mutation residue is likely to disrupt the amphipatic a-helical structure in helix B, which appears to be necessary for proper interaction of CaM wit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
17482572
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"Recent studies have shown that calmodulin (CaM) binds to the KCNQ2 and KCNQ3 C termini and may function as an auxiliary channel subunit XREF_BIBR, XREF_BIBR, XREF_BIBR."
19675672
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"CK2 phosphorylated SK2-bound CaM but not KCNQ2-bound CaM, thereby selectively regulating Ca 2+ gating of SK2 channels."
18701069
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"Additionally, we demonstrate that mutations that interfere with CaM binding to Kv7.2 and Kv7.3 reduced channel membrane abundance and activity, but these mutants retained zinc sensitivity."
36549648
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"CK2phosphorylated SK2 bound CaM but not KCNQ2 bound CaM, thereby selectively regulating SK2 channels."
18701069
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"Furthermore, in vitro assays have demonstrated that apoCaM or Ca 2+ -CaM can bind peptides containing the sequences of Kv7.2 hA or hB [ xref , xref , xref , xref , xref , xref ]."
30022004
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"To test whether CaM binding to KCNQ2 promotes trafficking of HA-KCNQ3 and KCNQ2 channels from the ER to the axon, we performed pulse-chase experiments after removal of BFA."
25077630
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"These data are entirely consistent with the concept that CaM bound to KCNQ2 acts as a Ca2+ sensor, conferring Ca2+ dependence to the trafficking of the channel to the plasma membrane and fully explaining the requirement of CaM binding for KCNQ2 function."
19494108
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"Our prediction thus supports these results by highlighting the importance of the interactions between KCNQ2 and the CaM proteins."
27307626
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"Considering the modest effect of CaM1234 on the axonal surface expression of HA-KCNQ3/KCNQ2 channels ( xref ), CaM bound to KCNQ2 may act as a Ca 2+ sensor for modulating not only the M-current, but also the channel density at the axonal membrane."
25077630
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"Calmodulin bound to the KCNQ2 subunit regulates channel trafficking and stabilizes channel activity."
24627475
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"CK2 phosphorylated SK2 bound CaM but not KCNQ2 bound CaM, thereby selectively regulating Ca 2+ gating of SK2 channels."
18701069
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"Here, we have studied this functional interaction using fluorescence and NMR spectroscopy, in order to compare the association between Kv7.2 and full-length CaM 1-148 with that between Kv7.2 and the isolated N- (CaM 1-78) and C-domain (CaM 79-148) fragments XREF_BIBR."
24489773
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"Although the binding of CaM with Kv7.2 is not fully recapitulated by its individual segments XREF_BIBR, this analysis helps in understanding how CaM interacts with the channel."
24489773
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"Given the importance that both groups ascribed to both of these regions for CaM binding to KCNQ2 subunits, we were surprised to find in the current work that IQ 2 , but not IQ 1 , produced a Ca 2+ -dependent gel shift of CaM."
12810850
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"First, we introduced two mutations within the IQ domain of KCNQ3 : an isoleucine to alanine substitution at the position 342 (KCNQ3-I342A); and an alanine substitution of the residues 346 to 349 (KCNQ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24333508
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"Since CaM interaction with KCNQ2 is required for functional expression of KCNQ channels in non-neuronal cells xref , xref , xref , we hypothesized that CaM regulates preferential targeting of KCNQ channels to the axonal surface."
25077630
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"In the present study, we show that the IQ motif of KCNQ3 regulates the formation of a stable CaM/KCNQ2/3 complex and the traffic of KCNQ2/3 channels at the AIS."
24333508
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"To probe for CaM interactions with KCNQ2–5, we performed immunoprecipitation (IP) experiments, followed by immunoblotting."
12810850
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"According to xref , calmodulin binding to KCNQ2 channels stabilized PI(4,5)P 2 channel binding."
24470487
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"These results suggest that a change in the configuration of CaM–KCNQ2 binding induced by elevated intracellular calcium led to the reduction in PIP2 affinity of the KCNQ2 channel."
24349250
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"Since A-kinase-anchoring protein (AKAP) 79 XREF_BIBR, XREF_BIBR regulates CaM binding to KCNQ2 XREF_BIBR and serves as an adaptor protein for CaM and PKC XREF_BIBR, XREF_BIBR, the mechanism responsible for CaM mediated trafficking of KCNQ channels to the axonal surface may well converge with the ability of CaM to modulate PKC dependent inhibition of M-current via AKAP79/150 XREF_BIBR, XREF_BIBR and PIP 2 XREF_BIBR."
25077630
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"To test whether CaM binding to KCNQ2 promotes trafficking of HA-KCNQ3/KCNQ2 channels from the ER to the axon, we performed pulse-chase experiments after removal of BFA."
25077630
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"CaM binds simultaneously to two sites of Kv7.2 in a 1∶1 stoichiometry xref ; xref ."
24489773
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"The current study suggests that not only the calcium-induced dissociation of CaM, but also a change in the configuration of CaM-KCNQ2 binding could suppress the KCNQ2 current."
24349250
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"Moreover, binding of WT CaM to KCNQ2 can moderately reduce the constitutive current through KCNQ2 homomeric channels by changing channel structure ( xref )."
23630338
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"In summary, it appears that the strength of the interaction of CaM with Kv7.2 channels is altered by Ca 2+ occupancy."
30022004
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"Both WT and dominant-negative CaM bind to the C terminus of KCNQ2 ( xref ) and (a) mutations in KCNQ2 that affect CaM binding, (b) expression of dominant-negative CaM, or (c) expression of a “CaM sponge” lead to retention of KCNQ2 homomeric channels in the ER ( xref ; xref ; xref )."
23630338
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"The structural elements critical for CaM binding to KCNQ2 lie in two conserved motifs in the proximal half of the channel C-terminal domain."
12223552
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"CK2phosphorylated SK2-bound CaM but not KCNQ2-bound CaM, thereby selectively regulating SK2 channels."
18701069
sparser
"These results together suggest that disruption of CaM binding to KCNQ2 impairs the trafficking of CD4-Q2C proteins from the ER to the AIS and distal axons."
25077630
reach
"Despite a modest reduction of CaM binding to KCNQ2 by the R353G mutation (XREF_FIG) XREF_BIBR, XREF_BIBR, the R353G mutant channels were localized to the AIS and axonal surface to a similar extent as the wild-type channels (XREF_FIG)."
25077630
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"Calmodulin (CaM) binds to two intracellular C-terminal segments of Kv7.2 channels, helices A and B, and it is required for exit from the endoplasmic reticulum."
24489773
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"The process appears to require at least two steps; the first involves the transient association of CaM with KCNQ2, and in the second, the complex adopts an "active" conformation that is more stable and is that which confers the capacity to exit the endoplasmic reticulum."
19494108
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"Disruption of CaM binding to KCNQ2 inhibits enrichment of HA-KCNQ3 and KCNQ2 channels at the axonal surface."
25077630
sparser
"In contrast, the BFNC R353G mutation located distal to the IQ motif modestly reduced but did not abolish CaM binding to KCNQ2 ( xref ) and had minimal effect on the polarized axonal surface expression of HA-KCNQ3/KCNQ2 channels ( xref )."
25077630
reach
"Given the importance that both groups ascribed to both of these regions for CaM binding to KCNQ2 subunits, we were surprised to find in the current work that IQ 2, but not IQ 1, produced a Ca 2+ -dependent gel shift of CaM."
12810850
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"In this study, we investigated the molecular mechanism of KCNQ2 current suppression mediated by calcium bound calmodulin."
24349250
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"We also demonstrated that a CaM deficient mutant channel, KCNQ2(R353G), showed augmented ionomycin-induced current suppression, which suggests that a change in the KCNQ2-CaM interaction is critical for the suppression."
24349250
sparser
"The second group found that both wt CaM and DN CaM interact with KCNQ2, consistent with our results that DN CaM can act as a dominant negative in CaM actions."
12810850
sparser
"Since the R353G mutation in KCNQ2 reduces CaM binding to heteromeric KCNQ2/KCNQ3 channels only by 20% xref , xref , our results suggest that a greater degree of impairment in CaM binding to KCNQ2 is needed to prevent targeting of heteromeric channels to the axonal surface."
25077630
reach
"These results together indicate that disruption of CaM interaction with KCNQ2 by the A343D mutation impairs the trafficking of HA-KCNQ3 and KCNQ2 channels from the ER to the axon."
25077630
reach
"Here we show that the L339R mutation in helix A, which is linked to human benign neonatal convulsions, perturbs CaM binding to KCNQ2 channels and prevents their correct trafficking to the plasma membrane."
19494108
sparser
"Despite a modest reduction of CaM binding to KCNQ2 by the R353G mutation ( xref ) xref , xref , the R353G mutant channels were localized to the AIS and axonal surface to a similar extent as the wild-type channels ( xref )."
25077630
sparser
"Disruption of CaM binding to KCNQ2 inhibits enrichment of HA-KCNQ3/KCNQ2 channels at the axonal surface."
25077630
sparser
"Disruption of CaM binding to KCNQ2 impairs trafficking of HA-KCNQ3/KCNQ2 channels from the ER to the axon."
25077630
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"According to XREF_BIBR, calmodulin binding to KCNQ2 channels stabilized PI (4,5) P 2 channel binding."
24470487
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"Of note, the signal of CaM 3 pulled down with Kv7.4 channels was stronger than WT CaM in the presence of 2 mM CaCl 2 , matching the observation by xref , who reported that longer exposure to calcium decreased CaM binding to Kv7.2 channels."
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