| 2009 |
Conserved negatively charged aspartates (CDD motif) in the A/B linker of the T1 tetramerization domain are required for efficient assembly of both homotetrameric Kv2.1 and heterotetrameric Kv2.1/Kv6.4 channels; arginine substitution in Kv6.4 at this position prevented its heterotetrameric interaction with Kv2.1, as shown by FRET and co-immunoprecipitation. |
Site-directed mutagenesis, co-immunoprecipitation, FRET (confocal microscopy), immunocytochemistry in HEK cells |
The Journal of biological chemistry |
High |
19717558
|
| 2008 |
Histidine 105 in the T1 domain of Kv2.1 is required for heteromerization with Kv6.4; H105V or H105R mutations disrupted T1–T1 interaction with Kv6.4 (and Kv6.3), prevented co-immunoprecipitation of Kv2.1 with Kv6.4, reduced FRET signal, and abolished Kv6.4-mediated shift in voltage dependence of activation. |
Yeast two-hybrid, FRET, co-immunoprecipitation, electrophysiology (two-electrode voltage clamp), dominant-negative co-expression |
The Journal of biological chemistry |
High |
19074135
|
| 2015 |
KCNE5 forms a triple complex with Kv2.1 and Kv6.4, modifying Kv2.1/Kv6.4 biophysical properties (accelerated activation, slowed deactivation, steepened inactivation slope, accelerated recovery from closed-state inactivation) without altering current density, as demonstrated by FRET and electrophysiology in HEK293 cells. |
Electrophysiology (patch clamp in HEK293 cells), FRET, immunocytochemistry |
Scientific reports |
High |
26242757
|
| 2015 |
4-AP potentiates Kv2.1/Kv6.4 currents by suppressing Kv6.4-mediated closed-state inactivation, recovering channels inactivated at resting potential; the lower half of the S6 domain (S6c) of Kv6.4 plays a crucial role in this 4-AP-induced potentiation, as shown by chimeric substitutions between Kv6.4 and Kv9.3. |
Electrophysiology (two-electrode voltage clamp in Xenopus oocytes), chimeric subunit substitutions |
PloS one |
High |
26505474
|
| 2018 |
The S6 activation gate of Kv6.4 contains atypical substitutions that restrict the functional stoichiometry of Kv2.1:Kv6.4 heteromers to 3:1 (Kv2.1:Kv6.4); two amino acid substitutions in the S6 gate of Kv6.4 limit formation and function of 2:2 heteromers, and substituting the self-compatible Kv2.1 T1 domain into Kv6.4 does not alter stoichiometry. |
Electrophysiology, concatemer/tandem dimer constructs, mutagenesis, comparative sequence analysis with cnidarian orthologs |
The Journal of general physiology |
High |
30322883
|
| 2011 |
Residues T203 in S1 and S347 in S5 of Kv2.1 are energetically coupled and interact with S4 residue R300; double mutant cycle analysis showed these specific S1–S4–S5 interactions are critical for Kv2.1 channel maturation and gating, and are important determinants for the functional Kv2.1/Kv6.4 chimeric channel. |
Chimeric Kv2.1/Kv6.4 channels, site-directed mutagenesis, double mutant cycle analysis, electrophysiology |
European biophysics journal |
Medium |
21455829
|
| 2020 |
KV6.4 traffics to the plasma membrane to modulate the voltage dependence of KV2.1 inactivation; the rare variant KV6.4-Met419 (rs140124801) fails to traffic to the plasma membrane, exerts a dominant-negative effect, and cannot modulate KV2.1 inactivation, resulting in a more depolarized voltage dependence of inactivation and a higher action potential threshold in neurons overexpressing the mutant. |
Functional expression in neurons, electrophysiology (patch clamp), plasma membrane trafficking assay, in vivo retrograde labeling of mouse uterine sensory neurons, human genetic association |
Cell reports |
High |
32697988
|
| 2017 |
Targeted deletion of Kv6.4 (Kcng4-/-) in mice causes male sterility due to disturbed spermiogenesis, manifested by severe reduction in sperm count, absence of motile spermatozoa, and abnormal sperm morphology (smaller head, shorter tail), indicating Kv6.4 is required for normal late-stage spermatogenesis. |
Knockout mouse model (targeted gene deletion), semen quality analysis, histology of testicular tissue |
Reproduction, fertility, and development |
High |
27677211
|
| 2014 |
Dlk1 activates expression of Kv6.4 (Kcng4) in motor neurons to modulate delayed-rectifier K+ currents, promoting a fast biophysical signature; Dlk1 inactivation shifts motor neurons toward slow biophysical properties and abolishes peak force outputs. |
Transgenic mouse and chick models, electrophysiology, transcriptome analysis, gain- and loss-of-function experiments |
Science |
High |
24626931
|
| 2024 |
The migraine-linked Kv6.4-L360P missense mutation in the S4-S5 linker significantly impairs function of Kv2.1/Kv6.4 channels; when expressed in fixed 2:2 stoichiometry (monomeric and tandem dimer configurations), L360P alters channel biophysical properties, providing a molecular mechanism for channel dysfunction in migraine. |
Electrophysiology with monomeric and tandem dimer (fixed stoichiometry) channel constructs in expression system |
Biochemical and biophysical research communications |
Medium |
39159549
|
| 2024 |
Kv6.4-L360P (migraine-linked variant) almost completely abolishes Kv2 currents when co-expressed with Kv2.1, proposed to act through a dominant-negative-like mechanism affecting the trigeminal system. |
Electrophysiology (heterologous expression with Kv2.1), molecular characterization of variant |
International journal of molecular sciences |
Medium |
39201645
|
| 2024 |
Two kcng4b mutations in zebrafish (kcng4b-C1 causing mild loss-of-function with C-terminal truncation, and kcng4b-C2 causing gain-of-function by forming an ectopic 7th transmembrane domain) produce distinct ear developmental defects (failure of kinocilia extension and ectopic otoliths for C1; absent otoliths and reduced kinocilia for C2), demonstrating that different functional states of the Kv6.4-containing channel regulate hollow organ development. |
Zebrafish mutant analysis, electrophysiology, developmental biology, in silico structural modelling |
Developmental biology |
Medium |
38492873
|
| 2025 |
Kv6.4 is specifically expressed in spinal motoneurons (not other spinal cord neuron classes) and co-clusters with Kv2.1 and Kv2.2 at endoplasmic reticulum-plasma membrane (ER-PM) junctions beneath C-bouton synapses; Kv6.4 clustering depends on Kv2.1 (severely reduced in Kv2.1 KO) and moderately on Kv2.2 (moderately reduced in Kv2.2 KO), and requires Kv2.1's ability to bind ER VAP proteins (absent in Kv2.1-S590A mutant). |
Immunofluorescence, transgenic/knockout mouse models (Kv2.1 KO, Kv2.2 KO, Kv2.1-S590A knockin), confocal microscopy, subcellular fractionation/localization |
The European journal of neuroscience |
High |
40919874
|
| 2025 |
In cortical parvalbumin (PV) neurons, Kv6.4 loss (Kcng4 KO) reduces action potential height and width, hyperpolarizes firing threshold and interspike potential, accelerates AP upstroke during repetitive firing, alters GABA release, and changes paired-pulse depression at PV→pyramidal synapses; effects are amplified at high-frequency firing, consistent with Kv6.4 reducing Kv2-mediated delayed rectifier current. |
Conditional/constitutive knockout mice, patch-clamp electrophysiology (intrinsic and synaptic), in vivo imaging of Kcng4 expression |
Proceedings of the National Academy of Sciences of the United States of America |
High |
41632839
|
| 2025 |
Dorsal root ganglion (DRG) neurons in mouse and human show predominantly RY785-resistant but GxTX-sensitive conductances, consistent with Kv2/KvS (including Kv6.4-containing) heteromeric channels, whereas superior cervical ganglion neurons show predominantly Kv2-only (RY785-sensitive) conductances; Kv6.4-containing channels are resistant to pore-blocker RY785 but sensitive to voltage-sensor modulator GxTX. |
Pharmacological dissection with two Kv2 inhibitors (RY785, GxTX), patch-clamp electrophysiology in native neurons (mouse SCG, mouse and human DRG) |
eLife |
High |
40423692
|
| 2025 |
In zebrafish, loss-of-function of kcng4b (modulatory subunit) or kcnb1 (Kv2.1, alpha subunit) reduces locomotor activity and induces seizures with pentylenetetrazole; mutants show increased c-fos and gad2 transcripts and decreased gabra1 transcripts, indicating disrupted inhibitory neurotransmission; local field potential recordings show increased spontaneous electrical activity in the optic tectum. |
Zebrafish loss-of-function mutants, behavioral assays, qRT-PCR, local field potential recordings |
bioRxivpreprint |
Medium |
40501962
|