Kv7.3

Description: potassium voltage-gated channel, KQT-like subfamily, member 3
Gene: Kcnq3
Alias: KV7.3, EBN2, BFNC2, KCNQ3

Edit - History

Introduction

KV7.3, encoded by KCNQ3, is a members of The potassium voltage-gated channel KQT-like subfamily. Kv7.3 is also known as: CNQ3; EBN2; BFNC2; FLJ37386; FLJ38392; DKFZp686C0248. Kv7.3 assembles with Kv7.2 to form the M channel, a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. NCBI [690].

Experimental data

Rat Kv7.3 gene in CHO host cells datasheet
Click for details 15 °C show 79 cells	Click for details 25 °C show 63 cells	Click for details 35 °C show 86 cells

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	3786	8	360234
Mouse	110862	15	300262
Rat	29682	7	295433

Edit

Transcript

Species	NCBI accession	Length (nt)
Human	NM_004519.4	11583
Mouse	NM_152923.3	11824
Rat	NM_031597.4	5798

Edit

Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	O43525	872
Mouse	Q8K3F6	873
Rat	O88944	873

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NM_004519.4

11583

NP_004510.1

872

transcript variant 1

isoform 1

NM_001204824.2

10696

NP_001191753.1

752

transcript variant 2

isoform 2 precursor

Predicted

XM_047421769.1

11547

XP_047277725.1

860

transcript variant X3

isoform X3

XM_011517026.3

28673

XP_011515328.1

752

transcript variant X2

isoform X2

XM_017013400.2

22988

XP_016868889.1

798

transcript variant X1

isoform X1

XM_054360446.1

11555

XP_054216421.1

860

transcript variant X3

isoform X3

XM_054360445.1

30244

XP_054216420.1

752

transcript variant X2

isoform X2

XM_054360444.1

22996

XP_054216419.1

798

transcript variant X1

isoform X1

Known

NM_152923.3

11824

NP_690887.2

873

Predicted

XR_875218.3

1894

transcript variant X2

XM_036159073.1

4726

XP_036014966.1

457

transcript variant X1

isoform X1

Edit

Post-Translational Modifications

PTM

Position

Type

Edit - History

Structure

Visual Representation of Kv7.3 Structure
Methodology for visual representation of structure available here

Basic structure of KCNQ2/3 proteins can be seen in figure 1 of [464] KCNQ3 is unusual because it has an alanine in the inner vestibule, three residues upstream of the signature GYG (see Fig.1A in [698]).

It is generally thought that KCNQ2/3 surface expression is governed by the intracellularC-terminal region, and that the pore region does not have any significant role in trafficking [705], [707], [708], [709], [73].

Kv7.3 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	6382.61	source
Mouse	5906.75	source
Rat	5290.06	source

Methodology for AlphaFold size prediction and disclaimer are available here

Edit - History

Kinetics

KCNQ2/KCNQ3 (See also Kv7.2 for more info)

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

Mutations in either KCNQ2 or KCNQ3 can cause the same phenotype (BFNC), and the expression of both subunits overlaps extensively, so they may combine to form a single channel. Expression of both subunits leads to larger currents with slightly changed gating kinetics and sensitivity to inhibitors. Furthermore, a KCNQ3 mutant modelled on a dominant-negative KCNQ1 mutation found in RWS inhibited KCNQ2 currents in a DOMINANT-NEGATIVE fashion [704]

SINGLE CHANNEL CONDUCTANCE

Single-channel and noise analysis indicated that homomeric KCNQ2 and KCNQ3 channels have conductances of roughly 18 and 7 pS, respectively. Co-expression did not increase the single-channel conductance, which varied between 8 and 22 ps. This variation suggested the formation of heteromers with different stoichiometries [463]

KCNQ2/3 in CHO cells

We used coexpression of GFP as a reporter for successful transfection, and only cells that fluoresced green were chosen for study using whole-cell clamp. CHO cells transfected with KCNQ2 and KCNQ3 expressed voltage-gated K+ currents with slow activation kinetics typical of KCNQ channels (Fig.1 A), whereas nontransfected CHO cells had negligible macroscopic K+ currents [68]

Edit - History

Expression and Distribution

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 Kv7.3 CHANNEL IN NEURON

In the hippocampal formation and cerebral cortex, KCNQ2 and KCNQ3 staining was detected on the somata and dendrites of many polymorphic and pyramidal neurons. Confocal immunofluorescence microscopy revealed that this somatodendritic staining was punctate in character and appeared to label both the cell surface and intracellular components (C). In the hippocampal formation, hilar polymorphic cells. ( E and H), CA3 pyramidal cells (F), and subicular pyramidal cells (G) exhibited somatodendritic staining for both subunits.

KCNQ2 and KCNQ3 proteins are colocalized in a somatodendritic pattern on pyramidal and polymorphic neurons in the human cortex and hippocampus. Immunoreactivity for KCNQ2, but not KCNQ3, is also prominent in some terminal fields, suggesting a presynaptic role for a distinct subgroup of M-channels in the regulation of action potential propagation and neurotransmitter release [1681]

The KCNQ2/3 subunits acquired an ankyrin G-binding motif, that allows them to concentrate at the nodes of Ranvier and the axonal initial segment (AIS) [702], [703]. KCNQ3 is a major determinant of M-channels location to the AIS [703] and displays a predominant intracellular distribution, whereas its combination with KCNQ2 leads to a large increase in axonal surface expression [706].

Edit - History

Function

Spontaneous mutations in Kv7.3, some producing a mere 25% reduction in function, cause human neonatal epilepsy [704], [705].

KCNQ2 and KCNQ3 play an important role in neonatal epilepsy. [462]

BNFC

Mutations causing benign familial neonatal convulsions were found to cause only slight reductions in current compared with wild-type controls, suggesting that small differences in the activity of these KCNQ channels in vivo might be sufficient to cause epilepsy [704]

Edit - History

Interaction

M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a anti-convulsant drug. NCBI

Expression of KCNQ2 and KCNQ3 individually yields only small currents, whereas their coexpression yields heteromeric currents 10-fold larger [695].

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]

Hydroxyl-Containing Residue at the 315 Position

Most of the wild-type KCNQ3 homomers, being well expressed at the plasma membrane, are functionally silent. Rearrangements of the pore-loop architecture induced by the presence of a hydroxyl-containing residue at the 315 position unlocks the channels into a conductive conformation. [73]

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]

KCNE1

KCNE1 slowed KCNQ2/3 currents and decreased their magnitude [1680]. However no significant effects have also been recorded when KCNE1 was co-expressed at levels that suffice to alter KCNQ1. An interaction of KCNQ2/3 with either KCNQ1 or KCNE1 would also seem physiologically irrelevant as neither has been detected in the CNS [704]

PIP

Native M-channels and expressed Kv7.2 + 7.3 channels are inhibited by stimulating Gq/11-coupled receptors – prototypically the M1 muscarinic acetylcholine receptor (M1-mAChR). The channels require membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to open and the effects of mAChR stimulation result primarily from the reduction in membrane PIP2 levels following Gq/phospholipase C-catalysed PIP2 hydrolysis. However, in sympathetic neurons, M-current inhibition by bradykinin appears to be mediated through the release and action of intracellular Ca2+ by inositol-1,4,5-trisphosphate (IP3), a product of PIP2 hydrolysis, rather than by PIP2 depletion [1744]