KCNH3 Membrane Protein Introduction

Introduction of KCNH3

KCNH3, also known as potassium voltage-gated channel subfamily H (eag-related) member 3, potassium channel voltage gated eag related subfamily H member 3, ether-a-go-go K(+) channel family member, KIAA1282, or Kv12.2, is a 117.1 kDa membrane protein that is composed of 1087 amino acids. In humans, it is encoded by the KCNH3 gene which is localized at the chromosome 12q13.12. The protein produced from the KCNH3 gene is a voltage-gated potassium channel alpha subunit and contains six transmembrane domains, a pore region of voltage-gated potassium channels, a cyclic nucleotide binding (CNB) domain, and N-glycosylation sites. It is showed forebrain-preferential distribution (such as cerebral cortex, amygdala, hippocampus, and striatal regions) by a 4-kb transcript, but not observed in any other tissue examined.

Basic Information of KCNH3
Protein Name Potassium voltage-gated channel subfamily H member 3
Gene Name KCNH3
Aliases Brain-specific eag-like channel 1, BEC1, Ether-a-go-go-like potassium channel 2, ELK channel 2, ELK2, Voltage-gated potassium channel subunit Kv12.2
Organism Homo sapiens (Human)
UniProt ID Q9ULD8
Transmembrane Times 6
Length (aa) 1083

Function of KCNH3 Membrane Protein

KCNH3 belongs to the ether-a-go-go (KCNH) family of voltage-gated potassium (K+) channels, which elicits an outward current both with transient and steady-state components voltage dependently. The transient part has fast-inactivating kinetics and the steady component reveals a bell-shaped current-voltage relationship, also observed in transcriptional regulator ERG, a member of the KCNH family. The K+ channels, mostly expressed in the central nervous system, are genetically heterogeneous and one of the determinants of neuronal excitability. The therapeutic potential of K+ channel blockers for cognitive enhancement has been reported, however, the contribution that each K+ channel gene makes to cognitive functions is still obscure. In cerebral cortexes, KCNH3 is widely present from layer II to layer VI, through specific expression in cell bodies of neurons with typical pyramidal shapes. Further investigation suggested that it is involved in cellular excitability of restricted neurons in the human central nervous system.

Characterization of spatial and temporal expression of Kcnh3 in the developing murine forebrain.Fig.1 Characterization of spatial and temporal expression of Kcnh3 in the developing murine forebrain. (Vezzali, 2016)

Application of KCNH3 Membrane Protein in Literature

  1. Takahashi S., et al. Neurochemical and neuropharmacological characterization of ASP2905, a novel potent selective inhibitor of the potassium channel KCNH3. Eur J Pharmacol. 2017, 810: 26-35. PubMed ID: 28552344

    The goal of this review was to identify the pharmacological profiles of a KCNH3 inhibitor N-(4-fluorophenyl)-N'-phenyl-N''-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine (ASP2905) in vitro and in vivo. The findings suggested that ASP2905 as a selective, orally administered inhibitor of KCNH3 can enhance cognitive performance.

  2. Vezzali R., et al. The FOXG1/FOXO/SMAD network balances proliferation and differentiation of cortical progenitors and activates Kcnh3 expression in mature neurons. Oncotarget. 2016, 7(25): 37436-37455. PubMed ID: 27224923

    This study provided further proofs on the FOXG1/FOXO/SMAD transcription factor network. The ligands of the TGFβ- and IGF-family, Foxo1, Foxo3 and Kcnh3 as novel FOXG1-target genes were determined during telencephalic developments and demonstrated that FOXG1 interfered with the Foxo1 and TGFβ transcription.

  3. Pan J., et al. Serum molecular signature for proliferative diabetic retinopathy in Saudi patients with type 2 diabetes. Mol Vis. 2016, 22: 636-645. PubMed ID: 27307695

    Six genes (KCNH3, DYX1C1, CCDC144NL, LOC100506476, LOC285847, and ZNF80) were selected and a combinatorial molecular signature was built based on their expressions. This study defined a combinatorial molecular signature seemingly useful as an attracting biomarker for early detections of proliferative diabetic retinopathy in diabetes patients.

  4. Csont T., et al. Tissue-specific gene expression in rat hearts and aortas in a model of vascular nitrate tolerance. J Cardiovasc Pharmacol. 2015, 65(5): 485-493. PubMed ID: 25626975

    Though the expression of 25 genes was found changed significantly in the heart (increased: Kcnh3, etc; decreased: Ihh, Fgfr1, etc), only 14 genes were altered in the aorta. It was the first pharmacogenomic analysis that nitroglycerin treatment resulting in vascular nitrate tolerance differentially affected the gene expression in vascular and cardiac tissues.

  5. Zhang X., et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nat Neurosci. 2010, 13(9): 1056-1058. PubMed ID: 20676103

    This article discovered that the voltage-gated K+ channel Kv12.2 was a potent regulator of excitability in hippocampal pyramidal neurons. The genetic deletion and pharmacologic block of Kv12.2 mainly reduced the firing threshold of these neurons. And the Kv12.2-/- (also referred to Kcnh3-/-) mice revealed signs of persistent neuronal hyperexcitability.

KCNH3 Preparation Options

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  1. Vezzali R, et al. (2016). The FOXG1/FOXO/SMAD network balances proliferation and differentiation of cortical progenitors and activates Kcnh3 expression in mature neurons. Oncotarget. 7(25): 37436-37455.

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