KCNH4 Membrane Protein Introduction

Introduction of KCNH4

KCNH4, also known as potassium voltage-gated channel subfamily H (eag-related) member 4, potassium channel voltage gated eag related subfamily H member 4, ether-a-go-go K(+) channel family member, or Kv12.3, is an approximately 111.7 kDa transmembrane protein containing 1017 amino acids. In humans, it is encoded by the KCNH4 gene, located on the chromosome 17q21.2. Human KCNH4 is a member of the ether-a-go-go (KCNH) family of voltage-gated potassium (Kv) channels and shares 89% sequence identity with rats. Analysis of human tissues reveals its expression only in brain and 4.4-kb, 7.5-kb, and 10-kb KCNH4 transcripts have been detected. Within the brain, KCNH4 is restricted to the telencephalon and predominantly present in striatal regions, including the putamen and caudate nucleus, but also expressed in the cerebral cortex and hippocampus.

Function of KCNH4 Membrane Protein

KCNH4 codes for a pore-forming alpha subunit of the voltage-gated Kv channel subfamily H, and is able to elicit an outward current with fast inactivation. Additionally, the expression of recombinant KCNH4 in mammalian cells induces a voltage-gated outward current without a fast inactivation component in some studies. The KCNH4 protein is brain-specific and resides in the neocortex and striatum, which possibly plays a role in the excitability of certain neurons in the human central nervous system (CNS). The voltage-gated Kv channel represents the most complex class of voltage-gated ion channels from structural and functional standpoints. Their varying functions involve regulating neurotransmitter release, neuronal excitability, heart rate, insulin secretion, cell volume, epithelial electrolyte transport, and smooth muscle contraction. KCNH4 is a protein-coding gene and several associated pathways with it including transmission across Kv channels and chemical synapses. There is an important paralog reportedly of this gene is potassium voltage-gated channel subfamily H member 8 (KCNH8), a member of the KCNH family.

Fig.1 MYC proteins preferentially target MA_hi genes. (Yang, 2017)

Application of KCNH4 Membrane Protein in Literature

1. Lopdell T.J., et al. DNA and RNA-sequence based GWAS highlights membrane-transport genes as key modulators of milk lactose content. BMC Genomics. 2017, 18(1): 968. PubMed ID: 29246110
   
   

   Fine mapping of the regions via imputed, whole genome sequence-resolution genotypes revealed protein-coding candidate causative variants impacting the KCNH4, ABCG2, DGAT1, STAT5B, NPFFR2, and RNF214 genes. These findings emphasized novel candidate genes and variants implicated in milk lactose regulation, which had effects on membrane transport mechanisms enhance key osmo-regulatory roles of lactose in milk.

2. Do A.N., et al. Whole exome analyses to examine the impact of rare variants on left ventricular traits in African American participants from the HyperGEN and GENOA studies. J Hypertens Manag. 2017, 3(1): pii: 025. PubMed ID: 29503979
   
   

   In gene-based analyses of this report, a statistically significant connection between KCNH4 and E/A ratio (P=8.7*10-8 using a burden test) was shown. Endonuclease G (ENDOG) was correlated with left atrial dimension (LAD) using the Madsen Browning weighted burden (MB) test.

3. Hu X.M., et al. The Tau-Induced Reduction of mRNA Levels of Kv Channels in Human Neuroblastoma SK-N-SH Cells. J Mol Neurosci. 2016, 58(2): 306-311. PubMed ID: 26576773
   
   

   In this study, the transfection of tau plasmids into human neuroblastoma SK-N-SH cells led to a significant decrease in mRNA levels of a number of Kv channels, such as Kv2.1, Kv3.1, Kv5.1, Kv9.2, and KCNH4. Accordingly, Kv currents recorded by patch-clamp technologies were substantially declined in tau-transfected SK-N-SH cells.

4. Li X., et al. Overexpression of tau downregulated the mRNA levels of Kv channels and improved proliferation in N2A cells. PLoS One. 2015, 10(1): e0116628. PubMed ID: 25590133
   
   

   Tau plasmids were transiently transfected into mouse neuroblastoma N2A cells to explore the possible linkages between tau and Kv channels. This treatment resulted in a downregulation of mRNA levels of certain Kv channels, including KCNH4, Kv2.1, Kv3.1, Kv4.1, and Kv9.2, but no distinct alteration was observed in KCNQ4 and Kv5.1.

5. Taugbøl A., et al. Small changes in gene expression of targeted osmoregulatory genes when exposing marine and freshwater threespine stickleback (Gasterosteus aculeatus) to abrupt salinity transfers. PLoS One. 2014, 9(9): e106894. PubMed ID: 25265477
   
   

   The main objective was to investigate the gene expression of three targeted osmoregulatory genes ATPA13, CFTR, and KCNH4 and one stress associated heat shock protein gene, HSP70, in gill tissues from marine and freshwater populations when exposed to a non-native salinity for periods ranging from 5mins to 3 weeks.

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Reference

1. Yang X H, et al. (2017). Incorporating genomic, transcriptomic and clinical data: a prognostic and stem cell-like MYC and PRC imbalance in high-risk neuroblastoma. BMC Syst Biol. 11(Suppl 5): 92.

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