Kv7.5

Description: potassium voltage-gated channel, KQT-like subfamily, member 5
Gene: Kcnq5
Alias: Kv7.5, KCNQ5

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Introduction

Kv7.5, encoded by the gene KCNQ5, is a member of the potassium voltage-gated channel KQT-like subfamily. Kv7.5 is differentially expressed in subregions of the brain and in skeletal muscle. The protein encoded by this gene yields currents (M current) that activate slowly with depolarization and can form heteromeric channels with the protein encoded by the KCNQ3 gene. NCBI

Experimental data

Rat Kv7.5 gene in CHO host cells datasheet
Click for details 15 °C show 50 cells	Click for details 25 °C show 65 cells	Click for details 35 °C show 77 cells

Rat Kv7.5 gene in HEK host cells
	Click for details 25 °C show 48 cells
Rat Kv7.5 gene in CV1 host cells
	Click for details 25 °C show 64 cells

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Gene

Species	NCBI gene ID	Chromosome	Position
Human	56479	6	576789
Mouse	226922	1	564251
Rat	259273	9	565799

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_019842.4	6364
Mouse	NM_001160139.1	6992
Rat	NM_001134643.2	3807

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Protein Isoforms

Multiple transcript variants encoding different isoforms have been found for this gene. NCBI

Species	Uniprot ID	Length (aa)
Human	Q9NR82	932
Mouse	Q9JK45	933
Rat	F1LY25	951

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NM_001160133.2

6421

NP_001153605.1

951

transcript variant 4

isoform 4

NM_019842.4

6364

NP_062816.2

932

transcript variant 1

isoform 1

NM_001160134.2

6034

NP_001153606.1

822

transcript variant 5

isoform 5

NM_001160132.2

6394

NP_001153604.1

942

transcript variant 3

isoform 3

NM_001160130.2

6337

NP_001153602.1

923

transcript variant 2

isoform 2

Predicted

XM_047419077.1

6226

XP_047275033.1

886

transcript variant X1

isoform X1

XM_024446493.2

1455

XP_024302261.1

407

transcript variant X4

isoform X4

XM_017011058.2

1974

XP_016866547.1

496

transcript variant X2

isoform X2

XM_024446492.2

1464

XP_024302260.1

423

transcript variant X3

isoform X3

XM_054355933.1

6222

XP_054211908.1

886

transcript variant X1

isoform X1

XM_054355936.1

1455

XP_054211911.1

407

transcript variant X4

isoform X4

XM_054355934.1

1974

XP_054211909.1

496

transcript variant X2

isoform X2

XM_054355935.1

1464

XP_054211910.1

423

transcript variant X3

isoform X3

Known

NM_001310477.1

7608

NP_001297406.1

924

transcript variant 3

isoform 3

NM_023872.3

6935

NP_076361.1

933

transcript variant 2

isoform 2

NM_001160139.1

6992

NP_001153611.1

952

transcript variant 1

isoform 1

Predicted

XM_036164276.1

13842

XP_036020169.1

822

transcript variant X1

isoform X1

Known

NM_001134643.2

3807

NP_001128115.2

951

Predicted

XM_039083095.1

7632

XP_038939023.1

923

transcript variant X2

isoform X2

XM_039083094.1

7659

XP_038939022.1

932

transcript variant X1

isoform X1

XM_039083096.1

7911

XP_038939024.1

507

transcript variant X3

isoform X3

XM_039083097.1

4394

XP_038939025.1

412

transcript variant X4

isoform X4

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Post-Translational Modifications

PTM

Position

Type

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Structure

Visual Representation of Kv7.5 Structure
Methodology for visual representation of structure available here

KCNQ channels have a membrane topology similar to the Kv channels, comprising six transmembrane-spanning segments (S1 –S6) with a typical S4 domain, which is the voltage sensor, a pore loop linking S5 and S6, and intracellular N and C termini. (Dupuis [138])

Kv7.5 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	8923.32	source
Mouse	6067.51	source
Rat	6536.78	source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

Human KCNQ5/Q3 in CHO cell Kinetics

Representative currents from a CHO-KCNQ5Q3 cells (elicited by a series of 3-s depolarizing steps, in the range −100 to +30 mV, in 10-mV increments from a holding potential of −80 mV). [1745]

KCNQ5 Kinetics expressed in X oocytes

[140] [724]

Currents activated very slowly (Fig.3 A) and were not fully activated even after 3-s test pulses. At lower step potentials, KCNQ5 currents showed a delay in activation, similar to KCNQ1 currents (32). In most cells (in 23 out of 28 oocytes) activation traces above +20 mV displayed a “crossover” phenomenon, which was observed independently of current amplitudes. Activation of KCNQ5 currents was generally slower than that of other KCNQ currents. Two components of deactivation, with time constants of 51 ± 2 and 281 ± 24 ms, were observed at a repolarizing voltage of −100 mV, following a 3-s depolarizing step to +40 mV (Table I). KCNQ1 tail currents display a characteristic “hook” indicative of recovery from inactivation (32, 33). We did not observe such a feature for KCNQ5 currents at voltages between −100 and +40 mV [140]

KCNQ5 yields currents that activate slowly with depolarization. [724] (Depuis [138])

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Expression and Distribution

Kv7.5 expression in the Brain

This includes prominent signals in the cortex, the occipital pole, frontal and temporal lobes, the caudate putamen, and the hippocampus [724] Kv7.5 is highly expressed in skeletal muscle [715] as well as certain regions of the brain [724]. Murine vascular smooth muscle cells only express a truncated form of KCNQ5. [139]

Localization of KCNQ5 in the normal and epileptic human temporal neocortex and hippocampal formation [1822]

Kv7.5 expression in body

KCNQ5 is expressed in skeletal muscle and shows widespread expression in the central nervous system. The expression of KCNQ5 is in many brain regions overlapping with the expression of KCNQ2 and KCNQ3 (Lerche et al., 2000 [140]; Schroeder et al., 2000 [724]).

KCNQ5 gene messages were present abundantly in murine vasculature (Ohya [1092], Yeung [1093]).

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CNS Sub-cellular Distribution

Kv7.5 Distribution in Neuron

Of its five known subunits, KCNQ5/Kv7.5 is extensively expressed in the central nervous system and it contributes to the generation of M-currents. The distribution of KCNQ5 was analyzed in auditory nuclei of the rat brainstem by high-resolution immunocytochemistry. Double labeling with anti-KCNQ5 antibodies and anti-synaptophysin or anti-syntaxin, which mark synaptic endings, or anti-microtubule-associated protein 2 (MAP2) antibodies, which mark dendrites, were used to analyze the subcellular distribution of KCNQ5 in neurons in the cochlear nucleus, superior olivary complex, nuclei of the lateral lemniscus, and inferior colliculus [1821]

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Function

Myoblast Proliferation

Kv7.5 is involved in myoblast proliferation [714].

M current

the function of KCNQ5 in the brain remains unknown and no neurological disorders have been attributed to it. Given KCNQ5’s similar biophysical properties to other members of the KCNQ family, KCNQ5 may also contribute to M-currents [461]

The Kv7 family is unique in the sense that mutations in four of the five genes have been linked to human hereditary diseases [722], [464].

KCNQ5 channels control resting properties and release probability of a synapse

Unlike most KCNQ channels, which are activated only by depolarizing stimuli, the presynaptic channels began to activate just below the resting potential. As a result, blockers and activators of KCNQ5 depolarized or hyperpolarized nerve terminals, respectively, markedly altering resting conductance. Moreover, the background conductance set by KCNQ5 channels, together with Na(+) and hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, determined the size and time course of the response to sub threshold stimuli [1820]

Mediates after-hyperpolarization

the function of KCNQ5 (Kv7.5), which also displays widespread expression in the brain, is entirely unknown. Here, we developed mice that carry a dominant negative mutation in the KCNQ5 pore to probe whether it has a similar function as other KCNQ channels. In the CA3 area of hippocampus, a region that highly expresses KCNQ5 channels, the medium and slow afterhyperpolarization currents are significantly reduced. In contrast, neither current is affected in the CA1 area of the hippocampus, a region with low KCNQ5 expression. Our results demonstrate that KCNQ5 channels contribute to the afterhyperpolarization currents in hippocampus in a cell type-specific manner [1746]

Myogenicity and Vasodilation in the Brain

In cerebral arteries, Kv7.4 and Kv7.5 proteins exist predominantly as a functional heterotetramer, which regulates intrinsic myogenicity and vasodilation attributed to CGRP. Surprisingly, unlike systemic arteries, Kv7 activity in MCAs is not affected by the development of hypertension, and CGRP (calcitonin gene-related peptide)-mediated vasodilation is well maintained. As such, cerebrovascular Kv7 channels could be amenable for therapeutic targeting in conditions such as cerebral vasospasm [1824]

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Interaction

KCNE channel alters KCNQ5 channel gating

The proteins KCNE1 and KCNE3 alter the gating of the Kv7.5 channel in Xenopus oocytes and HEK-293 cells. While KCNE1 slows activation and inhibits inward rectification, KCNE3 inhibits the current amplitude and differentially affects activation. Furthermore, KCNE1 increases Kv7.5 currents, when co-expressed in HEK cells. [710]

Calmodulin a Calcium sensor

Compared with other Kv channels, KCNQ channels have an extended intracellular carboxyl terminus that seems to be the target of many modulatory signals. Examples are modulation by Ca2+ [716], using calmodulin as the channel Ca2+ sensor [717], and regulation by plasma membrane phosphoinositides [718], [719], [720] perhaps in concert with protein kinase C [721].

Cell volume and Zinc

Changes in cell volume, extracellular Zn2+, acidification, and muscarinic receptor activation modulate Kv7.5 [723],[724].

KCNQ3

KCNQ5 forms heteromeric channels with KCNQ3, but not with KCNQ1, KCNQ2 or KCNQ4 (Lerche et al., 2000 [140]; Schroeder et al., 2000 [724]). KCNQ5 is inhibited by the M1 muscarinic receptor activation. (Depuis [138])

KCNQ2

Co-injection of KCNQ5 with the dominant negative mutant KCNQ2(G279S) (7) or of KCNQ2 with the equivalent mutant KCNQ5(G278S) leads to a roughly 50% reduction in current amplitude, which is consistent with a lack of interaction since only 50% of WT cRNA was injected [724]

BMS-204352, a KCNQ5 activator

Anti-ischemic compound, BMS-204352, strongly activates the voltage-gated K+ channel KCNQ5 in a concentration-dependent manner with an EC50 of 2.4 micro mol. Retigabine induced a smaller, yet qualitatively similar effect on KCNQ5. Furthermore, BMS-204352 (10 mM) did not significantly shift the KCNQ5 activation curves, as observed for the other KCNQ channels. The M-current blockers, linopirdine and XE991, inhibited the activation of the KCNQ5 channel induced by the BMS-204352. (Depuis [138])

Effect of Retigabine on KCNQ3/5 heteromeric channel

Retigabine induced concentration dependent leftward shifts in the KCNQ5/Q3 channel activation curve [1745]

M1 Muscarinic Inhibition

Currents expressed from KCNQ5 have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation