Channelpedia

Kv7.2

Description: potassium voltage-gated channel, KQT-like subfamily, member 2
Gene: Kcnq2
Alias: KV7.2, EBN, BFNC, EBN1, ENB1, HNSPC, KCNA11, KVEBN1, KCNQ2

Edit - History

Introduction

Kv7.2, encoded by KCNQ2, is a members of the potassium voltage-gated channel KQT-like subfamily.
Kv7.2 is also known as: KCNQ2; EBN; BFNC; EBN1; ENB1; BFNS1; EIEE7; HNSPC; KCNA11; KVEBN1.
Kv7.2 assembles with Kv7.3 to form the M channel, a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1) NCBI [690].

Edit - History

Gene

From an evolutionary perspective, KCNQ2 and KCNQ3 were the last KCNQ subunits to emerge, coincident with the apparition of myelin [701].

Species NCBI gene ID Chromosome Position
Human 3785 20 72447
Mouse 16536 2 59996
Rat 170848 3 59055
Edit - History

Transcript

At least five transcript variants encoding five different isoforms have been found for this gene. [464]

Species NCBI accession Length (nt)
Human NM_172107.4 9247
Mouse NM_010611.3 8301
Rat NM_133322.2 4158
Edit - History

Protein Isoforms

At least five transcript variants encoding five different isoforms have been found for this gene. [464]

Species Uniprot ID Length (aa)
Human O43526 872
Mouse Q9Z351 759
Rat O88943 852

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform
Edit

Post-Translational Modifications

PTM
Position
Type
Edit - History

Structure

Kv7.2
Visual Representation of Kv7.2 Structure
Methodology for visual representation of structure available here

STRUCTURE & MUTATION OF Kv7.2

Kv7.1 structure

Basic structure of KCNQ2/3 proteins and mutations leading to BFNC. KCNQ proteins have six transmembrane domains (TMDs) and a pore-forming P-loop. Mutations found in KCNQ2 (blue circles): Y284C, A306T, fs283, fs494 and spl516, spl397, fs534, fs616 and fs838. Numbering of KCNQ2 residues is according to KCNQ3 mutations (green squares). Several mutations truncate the channel before or in the A domain or the putative assembly domain, shown as beige and white boxes respectively. KCNQ4 mutations (red squares) identified in people with progressive dominant hearing loss DFNA2. With the exception of Fs71, these mutants exert dominant-negative effects. The L281S mutation73 has not been tested functionally. The equivalent tryptophan residue is mutated in KCNQ3 (W309R) and KCNQ4 (W276S), as well as in KCNQ1 in JLNS (W305S)74, indicating that it has no strong dominant-negative effect. G285 is the first glycine of the GYG pore signature sequence, which is also mutated in KCNQ1 in the dominant long-QT syndrome (G314S)75and suppresses wild-type KCNQ1 currents. Fs, frameshift mutation; spl, splice site mutation. Both types of mutations are expected to truncate the protein. c | Dendrogram of KCNQ and selected Kv channels [464]

Like all Kv channels, the KCNQ α subunits share a common core structure of six transmembrane segments with a voltage sensing domain (S1–S4) and a pore domain (S5 and S6)[696]. Sequence analysis predicts the presence of four helical regions (A–D) in all family members [697], and helices A and B constitute the binding site for calmodulin (CaM). [693] See figure 1 in [464] for the basic structure of KCNQ2/3 channels.

Mutation of the putative Gly hinge to Ala in KCNQ2 (Kv7.2) stops channel function.[77]

Kv7.2 predicted AlphaFold size

Species Area (Å2) Reference
Human 8867.25 source
Mouse 5842.30 source
Rat 9712.55 source

Methodology for AlphaFold size prediction and disclaimer are available here

Edit - History

Kinetics

KCNQ2/KCNQ3

KCNQ2/KCNQ3 heteromers yield currents with the properties of the M-current, see figure 2 in Jentsch's review [464].

Single Channel Kv7.2 Currents in CHO cells

Kv7.1 structure




Edit - History

Expression and Distribution

KCNQ2/KCNQ3

KCNQ2 and KCNQ3 were identified by homology to KCNQ1, and also by positional cloning in families with benign familial neonatal convulsions (BFNC), a neonatal form of epilepsy. Both subunits are expressed mainly in neuronal tissue including sympathetic ganglia, and their expression patterns in the brain overlap extensively. However, in situ hybridization indicates that they are not always expressed in the same ratio, and immunocytochemistry has shown that some neurons stain only for one or the other subunit. [464]

M-type channels are generated by the KCNQ (Kv7) family of voltage-gated subtypes [695], and they are found throughout the nervous system where they fulfil dominant roles in the control of excitability and neural discharges [464]. The M channel is slowly activating and deactivating potassium conductance important for determining the subthreshold electroexcitability in the central nervous system, especially in neocortical, thalamic, and hippocampal neurons. Therefore, heteromers of KCNQ2 with KCNQ3 or KCNQ5 forming M-type current potassium channels play a crucial role in the modulation of neuronal excitability. [694]

KCNQ2 and KCNQ3 are coexpressed on the cell bodies and dendrites of many hippocampal and cortical neurons. [461]

Edit - History

CNS Sub-cellular Distribution

DISTRIBUTION OF KCNQ2 in NEURON

Kv7.1 structure KCNQ2 (but not KCNQ3) neuropil staining also was detected in the inner, but not the outer, dentate molecular layer. It is in the dentate inner molecular layer that associational fibers derived from hilar mossy cells form en passante excitatory synapses on granule cell proximal dendrites. Because the granule cell dendrites extend radially through both inner and outer molecular layers, but the mossy cell axons and terminals are restricted to the inner layer, the KCNQ2 staining in the inner molecular layer seems most likely presynaptic. Thus, at least two types of hippocampal excitatory neurons (the mossy cells and granule cells) appear to express channels containing KCNQ2 but not KCNQ3 on their axons and/or termini, where they may regulate action potential propagation and neurotransmitter release [1681]

KCNQ2 plays a functional role at axonal initial segments and nodes of Ranvier.[339]

Edit - History

Function

Benign Familial Neonatal Convulsions are a rare epilepsy disorder with an autosomal-dominant inheritance. It is linked to mutations in the potassium channel genes KCNQ2 and KCNQ3. These encode for Kv7.2 and Kv7.3. [692] KCNQ2 mutation has implications for diagnosis and prognosis of familial neonatal seizures. [691]

further, KCNQ2/3 play a role in idiopathic generalized epilepsies and Rolandic epilepsy. [694]

Edit - History

Interaction

Calmodulin bound to KCNQ2 acts as a Ca2+ sensor, conferring Ca2+ dependence to the trafficking of the channel to the plasma membrane. [693]

Syntaxin 1A

Syntaxin 1A expressed with KCNQ2 homomeric channels resulted in a 2-fold reduction in macroscopic conductance and 2-fold slower activation kinetics.[58]

Extracellular H+ ions

Whole-cell and single-channel recordings demonstrated that extracellular H+ ions effect heterologously expressed KCNQ2/3 channels in the following way: KCNQ2/3 current was inhibited by H+ ions with an IC50 of 52 nM (pH 7.3) at -60 mV, rising to 2 microM (pH 5.7) at -10 mV. Neuronal M-current exhibited a similar sensitivity. I.e. extracellular H+ ions affected two distinct properties of KCNQ2/3 current: the maximum current attainable upon depolarization (Imax) and the voltage dependence of steady-state activation. [66]

Mepyramine and Diphenhydramine

Mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. Extracellular application of these drugs quickly and reversibly reduced KCNQ2/Q3 currents heterologously expressed in HEK293 cells. [72]

Meclofenamate and Diclofenac

Meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC(50) = 25 microM) and diclofenac (EC(50) = 2.6 microM) resulted in the activation of KCNQ2/Q3 K(+) currents by causing a hyperpolarizing shift of the voltage activation curve and markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel alpha subunits but they did not enhance KCNQ1 K(+) currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. [78]

CELECOXIB

Interestingly, celecoxib, a COX-2-specific inhibitor, has been shown to enhance Kv7.2–Kv7.5 currents overexpressed in HEK 293 cells with an EC50 of 2–5 µM. Previously, celecoxib had been shown to enhance Kv7.5 currents in A7r5 rat aortic smooth muscle cells and cause a vasodilatation of rat mesenteric arteries, whereas other COX-2-specific inhibitors, such as rofecoxib (Vioxx™; Merck & Co. Inc., Whitehouse Station, NJ, USA), had no effect on the currents [1675]

References

59

Xiong Q et al. Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers.
Proc. Natl. Acad. Sci. U.S.A., 2008 Feb 26 , 105 (3128-33).

66

Prole DL et al. Mechanisms underlying modulation of neuronal KCNQ2/KCNQ3 potassium channels by extracellular protons.
J. Gen. Physiol., 2003 Dec , 122 (775-93).

71

Fedorenko O et al. A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels.
Psychopharmacology (Berl.), 2008 Jul , 199 (47-54).

75

Maljevic S et al. Nervous system KV7 disorders: breakdown of a subthreshold brake.
J. Physiol. (Lond.), 2008 Apr 1 , 586 (1791-801).

77

Seebohm G et al. Differential roles of S6 domain hinges in the gating of KCNQ potassium channels.
Biophys. J., 2006 Mar 15 , 90 (2235-44).

80

Bentzen BH et al. The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels.
Neuropharmacology, 2006 Nov , 51 (1068-77).

270

Migliore M et al. Computer simulations of morphologically reconstructed CA3 hippocampal neurons.
J. Neurophysiol., 1995 Mar , 73 (1157-68).

339

Devaux JJ et al. KCNQ2 is a nodal K+ channel.
J. Neurosci., 2004 Feb 4 , 24 (1236-44).

461

Marrion NV Control of M-current.
Annu. Rev. Physiol., 1997 , 59 (483-504).

462

Dedek K et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel.
Proc. Natl. Acad. Sci. U.S.A., 2001 Oct 9 , 98 (12272-7).

464

Jentsch TJ Neuronal KCNQ potassium channels: physiology and role in disease.
Nat. Rev. Neurosci., 2000 Oct , 1 (21-30).

690

Yum MS et al. The first Korean case of KCNQ2 mutation in a family with benign familial neonatal convulsions.
J. Korean Med. Sci., 2010 Feb , 25 (324-6).

691

Goldberg-Stern H et al. Novel mutation in KCNQ2 causing benign familial neonatal seizures.
Pediatr. Neurol., 2009 Nov , 41 (367-70).

693

Alaimo A et al. Calmodulin activation limits the rate of KCNQ2 K+ channel exit from the endoplasmic reticulum.
J. Biol. Chem., 2009 Jul 31 , 284 (20668-75).

695

Wang HS et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel.
Science, 1998 Dec 4 , 282 (1890-3).

696

Haitin Y et al. The C-terminus of Kv7 channels: a multifunctional module.
J. Physiol. (Lond.), 2008 Apr 1 , 586 (1803-10).

1681

Cooper EC et al. Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy.
Proc. Natl. Acad. Sci. U.S.A., 2000 Apr 25 , 97 (4914-9).

Edit - History

Credits

Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/24/ , accessed on 2024 Apr 24


Add section