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Kv1.8


Synonyms: Kv1.8 kcna8 kcna10. Symbol:

Introductions


KCNA10 encodes the potassium voltage-gated channel, member 10 of the shaker-related subfamily, also known as Kcn1 and Kv1.8. This member of a shaker-related subfamily contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It is specifically regulated by cGMP and postulated to mediate the effects of substances that increase intracellular cGMP. This gene is intronless, and the gene is clustered with genes KCNA2 and KCNA3 on chromosome 1. [from http://www.ncbi.nlm.nih.gov/pubmed?Db=gene&Cmd=retrieve&dopt=fullreport&listuids=3744] KCNA10 is primarily expressed by hair cells of the inner ear [1654]

Genes


Human KCNA10 maps to chromosome 1 at p13.1 r p22.1. Finer mapping of the gene was achieved by PCR of a set of CEPH YAC clones that spanned the region of interest. YAC 818b9 contains human KCNA10. Human KCNA10 maps to 1p13.1 and resides within the genetic interval defined by microsatellite loci D1S2809 and D1S2726. That region of chromosome 1 contains another K channel gene, KCNA3. [611]

:

RGD ID Chromosome Position Species

Transcripts


Acc No Sequence Length Source

Ontologies


Accession Name Definition Evidence

Interactions


barium tetraethylammonium and 4-aminopyridine

KCNA10 currents are being blocked by classical K channel blockers (barium tetraethylammonium and 4-aminopyridine). It is also sensitive to inhibitors of cyclic nucleotide-gated (CNG) cation channels (verapamil and pimozide). The phorbol ester phorbol 12-myristate 13-acetate, an activator of protein kinase C, inhibited whole cell current by 42%. [612]

1.3

Interestingly, Kv1.3 and KCNA10 are located on chromosome 1 at p13.1 and are probably the result of gene duplication. Taken together, these data strongly suggest that KCNA10 has pharmacological properties common to both voltage-gated K channels and CNG cation channels [612]

kv1.4

Kcna10 is regulated in part by the soluble β subunit Kcna4b, which increases overall Kcna10 current and is currently thought to mediate upregulation of Kcna10 activity by cAMP and downregulation by cGMP [1655]

Verapimil

Kv1.3 Kinetics [612] Verapamil also inhibited KCNA10 current, with a Ki of 53 μM (n = 5) immediately. In the presence of verapamil, KCNA10 exhibited C-type inactivation (current at 0.8 s less than peak), suggesting that the block occurs in the open configuration.

KCNA4B

When injected alone in oocytes, KCNA4B produced no detectable current. However, when coinjected with KCNA10, it increased KCNA10 current expression by nearly threefold. In addition, the current became more sensitive to activation by cAMP. KCNA4B can be coimmunoprecipitated with the COOH terminus of KCNA10 and full-length KCNA10. It encodes a soluble protein (141 aa) with no amino acid homology to known beta-subunits but with limited structural similarity to the NAD(P)H-dependent oxidoreductase superfamily [610]

Proteins


KCNA10 shares 50–70% amino acid sequence identity with other KCNA protein family members [1654]

Structures


Structure of Kv1.8

KV1.8 contains six membrane-spanning domains with a shaker-type repeat in the fourth segment and a pore (P) region. Its most distinguishing feature is the presence of a putative cyclic nucleotide-binding (CNB) domain at the COOH terminus. It is specifically regulated by cGMP and postulated to mediate the effects of substances that increase intracellular cGMP1. The channel displays an unusual inhibitor profile, because in addition to being blocked by classical K+ channel blockers, it is also sensitive to inhibitors of cyclic nucleotide gated cation channel such as verapamil and pimozide [610]

KCNA10 is 90% identical to Kcn1 at the amino acid level, and its secondary structure is the same, including a putative cGMP-binding domain at the COOH terminus. [612]

Although KCNA10 is suspected to have a similar secondary structure to all KCNA channels it is unique among the KCNA family due to its putative cyclic nucleotide-binding domain at the carboxyl terminus [1654]

Distributions


KCNA10 protein was easily detectable at the apical membrane of rat proximal tubular cells, and a weaker signal was also evident in the glomerulus.[608].

Several types of voltage-gated K+ (Kv) channel, such as KCNQ1, KCNA10 and Kv1.3, are highly expressed at the apical membrane of proximal tubules and distal tubules. They may participate in stabilizing the cell membrane potential [1660]

Expressions


Expression in Tissue

KCNA10 is a cyclic nucleotide-gated, voltage-activated K channel that is detected in kidney, heart, and aorta by Northern blot. [608]

Subcellular Localization of Kv1.8

The aim of this study was to establish the cellular and subcellular localization of KCNA10 in kidney and vascular tissues. An anti-KCNA10 polyclonal antibody was generated, and immunocytochemical studies were performed on rat kidney. KCNA10 protein was easily detectable at the apical membrane of rat proximal tubular cells, and a weaker signal was also evident in the glomerulus. In situ hybridization experiments confirmed the immunocytochemical studies and revealed KCNA10 expression in human proximal tubular cells, glomerular and vascular endothelial cells, and also in vascular smooth muscle cells. The data suggest that KCNA10 may facilitate proximal tubular sodium absorption by stabilizing cell membrane voltage [608]

KCNA10 Not expressed in Brain

Multiple organs from the adult Kcna10TM45 were examined for beta-galactosidase (Kcna10 promoter and enhancers) expression. Brain, heart, lung, and liver from heterozygous and homozygous Kcna10TM45 mice did not exhibit any beta-galactosidase expression. Kidney expression could not be evaluated due to endogenous beta-galactosidase-like activity in the wild type kidney [1654]

KCNA4B's message expression parallels, to a large extent, that of KCNA10, with predominant expression in heart, kidney, and skeletal muscle, but not in brain [610]

Hair cells of the inner ear

In hair cells of the Corti organ KCNA10 shows strong expression.[1655]

KCNA10 is primarily expressed in hair cells in the vestibular organs and the organ of Corti in the inner ear as was also shown by a study using reporter genes. KCNA10 expression follows a gradient opposite to the tonotopic gradient. However, KCNA10 null mice displayed mild hearing deficits and significant but not overt vestibular dysfunction. [1654]

Functionals


Root cells

Vascularization

Kv1.8 participates in renal K metabolism and regulates vascular tone. [608]

Auditory function

A recent study showed that a null mutation of mouse KCNA10 causes significant vestibular and mild hearing dysfunction [1654]

QT Syndrome

In addition KCNA10 has been associated with Long QT syndrome (LQTS), an arrhythmogenic disorder characterized by prolongation of the QT interval on electrocardiograms (ECGs) [611]

Disorientation

The KCNA10-null mouse does not exhibit any obvious imbalance behaviors such as circling, weaving, or head-bobbing, and swimming behavior that relies on the gravity sensing organs was normal [1654]

Kinetics


Kv1.8

Kv1.3 Kinetics [612] whole cell KCNA10 currents recorded from a Xenopus laevis oocyte under 2-electrode voltage clamp, showing that KCNA10 behaves as a voltage-gated channel with a threshold voltage around −10 mV. Note that ensemble KCNA10 currents exhibit minimal steady-state inactivation. Inset: voltage protocol with holding potential of −80 mV and test pulses from −60 to +50 mV in 10-mV steps [612]

Single Channel Kinetics

Kv1.3 Kinetics [612] Single-channel conductance of hKCNA10 is ∼11 pS. A: representative single hKCNA10 channel currents recorded from an inside-out membrane patch excised from an oocyte that expressed 2.5 mA of whole cell current at +40 mV

Models


Hodgkin and Huxley Model of Kv1.8

Kv1.3 Kinetics [612] Activation parameters were determined by using the Pulse-Fit program (Heka), and the observed currents were fitted to a variant of the Hodgkin-Huxley equation. The time constant of activation (τact) was determined by using voltage steps from −60 to +40 mV from a holding potential of −80 mV. An example of an activation curve (from −80 to +40 mV) fit by an exponential is shown

References


[604 : 20628086]
[605 : 19913121]
[606 : 16382104]
[607 : 12477932]
[609 : 7789190]
[611 : 9177773]
[613 : 7519783]
[612 : 10836990]
[1660 : 15300162]
[608 : 12444201]
[1793 : 20393778]
[610 : 12060596]
[1654 : 23528307]
[2047 : 24252178]
[1655 : 22446089]

Credits


Editor : Admin.

Contributors : Rajnish Ranjan, Michael Schartner, Nitin Khanna

To cite : [Editor], [Contributors]. Accessed on [Date] Channelpedia , http://channelpedia.epfl.ch/ionchannels/8