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kcnh1

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Official Full Name
potassium voltage-gated channel, subfamily H (eag-related), member 1
Background
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms.
Synonyms
KCNH1; potassium voltage-gated channel, subfamily H (eag-related), member 1; potassium voltage-gated channel subfamily H member 1; eag; eag1; h eag; Kv10.1; Voltage gated potassium channel subunit Kv10.1; MGC124420; MGC142269; EAG channel 1; Ether a go go potassium channel 1; Ether-a-go-go potassium channel 1; h-eag; hEAG1; KCNH1_HUMAN; M eag; MGC124419; Potassium voltage gated channel subfamily H (eag related), member 1; Voltage-gated potassium channel subunit Kv10.1; OTTHUMP00000034451; OTTHUMP00000034569; ether-a-go-go, Drosophila, homolog of

Recent Research

KCNH1 (potassium channel, voltage-gated, subfamily h, member 1) encodes a voltage-gated potassium channel (Kv10.1). Kv10.1 is mainly found in the brain among normal tissues, but it is also expressed in myoblasts, placenta, testis, and adrenal gland. In myoblasts, Kv10.1 channel activity provides the hyperpolarization needed just before cell fusion. In the nervous system, it contributes to the control of neuronal excitability.

Molecular and biophysical characteristics of Kv10.1

In humans, Kv10.1 is located at 1q32.1–32.3. This is a relatively large locus for a potassium channel, with 11 exons and large introns. The gene spans over more than 500,000 bp. Four alternative transcripts have been identified in the human channel.

The function of KV10.1 is strongly modulated by many factors. Intracellular Ca2+ is able to inhibit Kv10.1; such inhibition seems to be due to interaction with calmodulin at three defined domains in the channel and/or by the Ca-binding protein S100B, which uses the same binding sites. Kv10.1 is also regulated by low extracellular pH which shifts its conductance/voltage relationship toward more depolarized potentials and slows its activation gating. External protons also reduce the ability of Mg2+ to slow voltage-dependent activation of Kv10.1.

Deregulation of Kv10.1 expression in cancer

It is reported that cells transfected with Kv10.1 are able to grow in the absence of serum, loose contact inhibition, and induce aggressive tumors when implanted into immune-depressed mice. In experiments performed in vivo, the expression of Kv10.1 favors xenograft tumor progression in immunodeficient mice. Kv10.1 inhibition using a specific monoclonal antibody reduces the tumor growth in vivo, while oral doses of astemizole also reduce the progression of subcutaneous tumors and the frequency of metastasis in lung carcinoma. Moreover, the involvement of histone acetylation of KCNH1 has been reported to regulate the expression of Kv10.1 in head and neck squamous carcinoma cells. Recently, the methylation of KCNH5 gene that encode for Kv10.2 was identified in lung cancer. Kv10.1 channel expression is also regulated by other cancer-associated factors including estrogen receptors (ERα) and human papillomavirus (HPV) oncogenes (E6/E7). Estrogens (E2) up-regulate Kv10.1 channel expression in cancer cells in a cell type-dependent manner. Moreover, cervical cancer cells and keratinocytes expressing HPV oncogenes displayed Kv10.1 expression in contrast to normal keratinocytes.

Kv10.1 regulates cell migration in the more aggressive cancer phenotypes

Kv10.1 has been first demonstrated to regulate migration in leukemia cells. Inhibition of Kv10.1 resulted in reduction of both cell proliferation and migration in high-expressing Kv10.1 cells and high-migrating cells, respectively. It is therefore possible that Kv10.1 plays a dual role in cancer cells according to the tumor phenotype. In breast cancer, Kv10.1 is expressed both in non-invasive MCF-7 and invasive MDA-MB-231 cells, and its expression is up-regulated in invasive breast carcinoma. In this type of cancer, Kv10.1 has been shown to be involved in both agonist and serum-induced membrane hyperpolarization that lead to Ca2+ entry, cell cycle progression, and therefore to cell proliferation in the non-invasive MCF-7 cells.

Kv10.1 up-regulates the expression of HIF-1α

The tumor microenvironment (TM) is a complex structure composed of a largely modified extracellular matrix (ECM) along with accompanying factors, which represents an active substrate for tumorigenesis as well as a determinant of treatment outcome. The best characterized hypoxic sensor is the alpha sub- unit of the hypoxia-inducible factor 1 (HIF-1α), an important transcriptional factor that controls the expression of hundreds of genes involved in angiogenesis, induction of glycolytic enzymes in tumor tissues, modulation of cancer cell cycle, cancer proliferation, and cancer metastasis . Interference with the cellular oxygen homoeostasis system was proposed as a potential mechanism for the oncogenic role of Kv10.1. When these Eag1-expressing cells were implanted into severe combined immune deficient (SCID) mice, tumors were induced; it has been found that both Kv10.1 and HiF-1α are over-expressed in breast cancer tissues compared with matched normal tissue. Both proteins are co-expressed in breast cancer tissues, and their expressions decreased with BMI before surgery, tumor size, invaded lymph node, and tumor stage.

In a word, Kv10.1 channel is present in all metazoans, and remarkably in the mammalian brain, but also often over-expressed in tumor cells where it has been reported to have oncogenic properties and to regulate cell proliferation, survival, and angiogenesis (Figure 1). Emerging data shows its contribution in migration and invasion, key steps in metastasis, in aggressive cancer phenotypes (Figure 1).

kcnh1Figure 1. An overview summarizing our knowledge of the factors that regulate Kv10.1expression and or activity inhuman cancers and how it impacts the cancerogenesis process

References:

  1. Ouadidahidouch H, et al. Kv10.1 K+ channel: from physiology to cancer. Pflügers Archiv - European Journal of Physiology, 2016, 468(5):751-762.
  2. Simons C, et al. Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. Nature Genetics, 2015, 47(3):304.
  3. Mastrangelo M, et al. Epilepsy in KCNH1-related syndromes. Epileptic Disorders, 2016, 18(2):123-136.