Disease relevance of KCNH1

• Antisense experiments against eag reduce cell proliferation in some cancer cell lines, and inhibition of EAG-mediated currents has been suggested to decrease cell proliferation in a melanoma cell line [1].
• Using RT-PCR we investigated healthy human brain and human gliomas of different subtypes and malignancy grades for the expression of human EAG1 and eag-related gene (ERG) 1 channels. mRNA of both channels was detected in all tissues [2].
• We examined transcripts for Kv1.3, h-erg, h-eag, and BEC1 genes in primary lymphocytes and leukemias and in several hematopoietic cell lines [3].
• Characterization of an eag-like potassium channel in human neuroblastoma cells [4].
• EAG repair technical success (aneurysm exclusion, graft patency, patient survival) at 30 days was 89.2% [5].

High impact information on KCNH1

• Heteromultimeric interactions among K+ channel subunits from Shaker and eag families in Xenopus oocytes [6].
• Inhibition of EAG expression in several of these cancer cell lines causes a significant reduction of cell proliferation [7].
• We have investigated the possible implication of the cell cycle-regulated K(+) channel ether à go-go (EAG) in cell proliferation and transformation [7].
• We show that transfection of EAG into mammalian cells confers a transformed phenotype [7].
• Advances made in cloning K+ channel subunits of the Kv, eag, Kir, and IsK families are discussed, and progress made in identifying the K+ channel subunits expressed in the mammalian myocardium is summarized [8].

Biological context of KCNH1

• In the electrophysiological study, NPMM-differentiated hMSCs expressed two delayed rectifier K(+) currents related to two ether-??-go-go K(+) channels (eag1, eag2), which are fundamental for setting the negative resting potentials required for neuronal survival and basal cell activity [9].
• Immunochemistry experiments showed the presence of EAG channel protein in cells from the primary cultures and in cervical cancer biopsies sections from the same patients [1].
• The h-eag gene was localized to chromosome 1q32-41, and is expressed as a approximately 9 kb transcript in myogenic cells and in adult brain tissue [10].
• 3. h-eag shows a marked Cole-Moore shift, i.e. the activation kinetics become very slow when the depolarization starts from a very negative holding potential [4].
• 5. When cells were grown in the presence of 10 microM retinoic acid in order to synchronize the cell line in the G1 phase of the cell cycle, h-eag current was reduced to less than 5 % of the control value, while the delayed rectifier channel was expressed more abundantly [4].

Anatomical context of KCNH1

• Upon expression in mammalian cells and Xenopus laevis oocytes, we investigated the inhibition of the closely related hEAG1 and hEAG2 channels by agents that have previously been reported to block hERG1 channels [11].
• Neural differentiation of human mesenchymal stem cells: evidence for expression of neural markers and eag K(+) channel types [9].
• In addition, human EAG mRNA is detected in several somatic cancer cell lines, despite being preferentially expressed in brain among normal tissues [7].
• In normal tissues, EAG mRNA is almost exclusively expressed in brain, but it is expressed in several somatic cancer cell lines, including HeLa, from cervix [1].
• We have isolated the full-length coding region of a human ether-a-go-go K+ channel (h-eag) from myoblasts undergoing differentiation [10].

Associations of KCNH1 with chemical compounds

• A modeling approach that allowed for partial conformational relaxation of hEAG model structures upon ligand docking suggests that high-affinity block of ether à go-go channels is mediated by an anchoring of the clofilium alkane tail between S6 and the pore helices [11].
• Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels [12].
• 6. Acute application of 10 microM retinoic acid blocked the delayed rectifier channel but enhanced the h-eag current [4].
• Selective deletion of the HERG-specific sequence (HERG Delta138-373) located between the conserved initial amino terminus (the eag or PAS domain) and the first transmembrane helix accelerates channel activation and shifts its voltage dependence to hyperpolarized values [13].
• 3 The block of hEAG1 channels by LY97241 and clofilium was time-, use-, and voltage-dependent, best explained by an open-channel block mechanism [14].

Other interactions of KCNH1

• In this study, we used chimeras constructed from hERG and ether-a'-go-go (EAG) channels to identify interactions between residues in the S4-S5 linker and S6 domain that were critical for stabilizing the channel in a closed state [15].
• However, its voltage dependence was smaller and, therefore, hEAG2 channels start to open at more negative voltages than hEAG1 [16].
• KCR1 also accelerates the activation of rat EAG K+ channels expressed in Xenopus oocytes or in COS-7 cells [17].
• The technique is demonstrated here using the human ether-a-go-go potassium channel and the kinase SRC [18].

Analytical, diagnostic and therapeutic context of KCNH1

• Reverse transcription-PCR and Southern-blot experiments revealed eag expression in 100% of the cancerous samples and in 33% of the normal biopsies [1].
• Far-Western blotting revealed that KCR1 and EAG proteins interacted with each other by means of their C-terminal regions [17].
• Site-directed mutagenesis indicates that the eag carboxyl terminus is crucial for this interaction, exerting effects preferentially on N-type inactivation [6].
• The suppressive factor as well as the capacity to restore EAG rosette formation by modulated lymphocytes were destroyed by heating (56 degrees C, 30 min) or by freezing and thawing [19].
• This study reports a multicenter EAG repair versus COS repair parallel cohort trial at 12 months and additional observations of specific device failure types and their impact on an aortic endograft design beyond that follow-up period [5].

References