Channelpedia

Kv6.4

Description: potassium voltage-gated channel, subfamily G, member 4
Gene: Kcng4
Alias: Kv6.4, kcng4

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Introduction

Kv6.4 (also known as KV6.4; MGC4558; MGC129609), encoded by the gene KCNG4, is a member is a gamma subunit of the voltage-gated potassium channel, subfamily G. Kv6.4is electrically silent as it is not capable of forming function homotetrameric channels. It can heterotetramerize with Kv2.1 α-subunits to form functional Kv2.1/Kv6.4 channel complexes and is predominantly found in the brain NCBI

Experimental data

Rat Kv6.4 gene in CHO host cells       datasheet

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35 °C
show 58 cells
Mouse Kv6.4 gene in CHO host cells       datasheet

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show 32 cells
Human Kv6.4 gene in CHO host cells       datasheet

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Gene

Species NCBI gene ID Chromosome Position
Human 93107 16 21355
Mouse 66733 8 11904
Rat 307900 19 12103
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Transcript

Species NCBI accession Length (nt)
Human NM_172347.3 5503
Mouse NM_025734.2 3822
Rat NM_001107435.1 4083
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Protein Isoforms

Species Uniprot ID Length (aa)
Human Q8TDN1 519
Mouse Q80XM3 506
Rat D4AD66 506

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform
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Post-Translational Modifications

PTM
Position
Type
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Structure

Kv6.4
Visual Representation of Kv6.4 Structure
Methodology for visual representation of structure available here

Eight different voltage-gated K+ (Kv)3 Shaker-related channel subfamilies (Kv1–Kv6 and Kv8–Kv9) have been identified based on the degree of sequence homology [606]. Fully assembled Kv channels are composed of four α-subunits arranged around a central pore. Each α-subunit consists of six transmembrane segments S1–S6 with a cytoplasmic N and C terminus. The N terminus contains the T1 domain, a tetramerization domain that facilitates the assembly of α-subunits into functional channels. The presence of a T1 domain is not absolutely required for channel assembly because subunits without a T1 domain could also assemble into a functional tetramer, although less efficiently [677], [678], [679]. However, the T1 domain not only promotes but also restricts the formation of possible homo- and heterotetramers by preventing incompatible subunits from assembling [680], [660]. When four compatible T1 domains assemble, they are arranged with the same 4-fold symmetry as the transmembrane segments, forming a hanging gondola structure [681].

Kv6.4 predicted AlphaFold size

Species Area (Å2) Reference
Human 6401.32 source
Mouse 4771.59 source
Rat 4988.83 source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

Human Kv6.4 Kinetics with Rat Kv2.1 in HEK293 Cells

Kv1.1 structure Kv6.4 exerts several changes in the biophysical properties of Kv2.1 in Kv2.1/Kv6.4 channel complexes: a decrease in the current density [14] and a hyperpolarizing shift in the voltage-dependence of inactivation by ~40 mV, but without any significant effects on voltage-dependence of channel activation [15]. Here we show the modulating effects of Kv6.4 on Kv2.1 gating properties by analyzing the voltage-dependence of VSD movements in Kv2.1 and Kv2.1/Kv6.4 channels from IQ recordings. Our results suggest that Kv6.4 subunits display an intrinsic voltage-dependency with an operational VSD in heterotetrameric Kv2.1/Kv6.4 channels, by virtue of which it specifically influences the voltage-dependent inactivation properties of Kv2.1 [1838]

Kv6.4 with Kv2.1 in HEK293 Cells

Kv1.1 structure Human Kv constructs were cloned in the mammalian vector peGFP-N1 (Clontech, Palo Alto, CA, USA). The Kv6.4 construct in which the C-terminus was exchanged for that of Kv3.1 as well as the N- and C-terminal segment constructs were constructed by PCR amplification using the QuickChange Site-Directed Mutagenesis kit (Stratagene La Jolla, CA, USA) and mutant primers. The main biophysical effect of WT Kv6.4 in a functional Kv2.1/Kv6.4 heterotetrameric channel is the approximately 40 mV hyperpolarizing shift in the voltage dependence of inactivation compared to Kv2.1 homotetramers. Indeed, the midpoint of inactivation for homotetrameric Kv2.1 currents was −23 mV which was shifted to −59 mV in heterotetrameric Kv2.1/Kv6.4 channels [1841]

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Biophysics

Markov Model for Kv2.1/Kv6.4 Channel Gating

Kv1.1 structure For convenience we used a simplified gating model (A) with a single transition between closed (C) and activated (A) state for each subunit, followed by the concerted step into the open (O) state (after all four subunits have reached the A-state). The equivalent Markov state-model (B) was built such that it could simulate both the heterotetrameric Kv2.1/Kv6.4 channel configuration with a 3[ratio]1 stoichiometry, as well as the homotetrameric Kv2.1 channel. To represent the heterotetrameric stoichiometry the closed and activated state of the Kv6.4 subunit are indicated with asterisks (C and A, respectively) [1838]

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Function

Domains Required for Kv6.4 Function

It has been demonstrated that Kv2.1 chimeras containing either S1 or S5 from Kv6.4 were functional, wheras a chimeric Kv2.1 subunit containing both the Kv6.4 S1 and S5 segments did not form functional channels. However, back mutation of some residues in this S1/S5 chimera restored functionality, and it was shown that interactions between S1, S4, and S5 are important for the functionality of WT Kv2.1 (4). It is possible that the inability to form electrically functional channels in homotetrameric configuration is due to the lack of such S1/S4/S5 interactions, at least in the case of Kv6.4 [1840]

His-105 in the T1 domain of Kv2.1 is required for functional heteromerization with members of the Kv6 subfamily, such as Kv6.4. [664]

Migraine

Several genes encoding potassium channels, including KCNK18, KCNG4, and KCNAB3, were identified as potentially linked to migraine [1839]

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Interaction

Aspartates in the T1 domain are required for efficient assembly of both homotetrameric Kv2.1 and heterotetrameric Kv2.1/silent Kv6.4 channels. [677]

References

664

Mederos Y Schnitzler M et al. Mutation of histidine 105 in the T1 domain of the potassium channel Kv2.1 disrupts heteromerization with Kv6.3 and Kv6.4.
J. Biol. Chem., 2009 Feb 13 , 284 (4695-704).

665

Rudy B Diversity and ubiquity of K channels.
Neuroscience, 1988 Jun , 25 (729-49).

674

Tu L et al. Voltage-gated K+ channels contain multiple intersubunit association sites.
J. Biol. Chem., 1996 Aug 2 , 271 (18904-11).

678

Kobertz WR et al. K+ channels lacking the 'tetramerization' domain: implications for pore structure.
Nat. Struct. Biol., 1999 Dec , 6 (1122-5).

679

Zerangue N et al. An artificial tetramerization domain restores efficient assembly of functional Shaker channels lacking T1.
Proc. Natl. Acad. Sci. U.S.A., 2000 Mar 28 , 97 (3591-5).

680

Lee TE et al. Structural determinant for assembly of mammalian K+ channels.
Biophys. J., 1994 Mar , 66 (667-73).

681

Kobertz WR et al. Hanging gondola structure of the T1 domain in a voltage-gated K(+) channel.
Biochemistry, 2000 Aug 29 , 39 (10347-52).

1839

Lafrenière RG et al. Identification of novel genes involved in migraine.
Headache, 2012 Oct , 52 Suppl 2 (107-10).

1840

Bocksteins E et al. Electrically silent Kv subunits: their molecular and functional characteristics.
Physiology (Bethesda), 2012 Apr , 27 (73-84).

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Credits

Contributors: Katherine Johnston

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/22/ , accessed on 2024 Dec 21


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