Kv12.1

Kv12.1, encoded by the gene KCNH8, is a voltage-gated potassium channel, pore-forming (alpha) subunit, subfamily H. Kv12.1 is also known as ELK, ELK1, and elk3.

Visual Representation of Kv12.1 Structure
Methodology for visual representation of structure available here

Kv12.1 Crystal Structure

Ribbon diagram of the Elk-1−E74DNA complex viewed from the C-terminal end of the alpha3 DNA recognition helix. The alpha-helices are light blue and beta-strands are yellow. The DNA is red and GGA core is green. The two residues distal to the DNA binding surface, Asp 69 and Asp 38, which affect the DNA binding properties, are colored in [1782]

rat Kv12.1 expressed in CHO cells

In rat elk1-transfected CHO cells, this protocol elicited slowly activating outward currents at test potentials positive to −70 mV. During the 2 s test pulses, RELK1-mediated outward currents did not inactivate. This behaviour was reminiscent of REAG-mediated outward currents. When test potentials were terminated by stepping back to the original holding potential of −120 mV, slowly deactivating tail currents were observed In Xenopus [809]

Kv12.1 recorded in Xenopus oocytes

In Xenopus oocytes injected with human KCNH8 cRNA robust, slowly activating K+ currents were recorded. KCNH8 outward currents were resolved at potentials above -90 mV in regular ND96 solution. Kv12.1 opens at hyperpolarized potentials with the half-maximal activation at -62.4 mV.[808].

Zebrafish Elk channel recorded in X oocytes

Zebrafish ELK channels were activated by depolarizing voltage steps and showed inactivation at voltages >+40 mV. The half-maximal activation voltage (V1/2) was −45.3 ± 3.2 mV (n = 18) with a slope of e-fold per 13.8 ± 0.6 mV (n = 18). In comparison, human ELK2 channels activate with V1/2 of −22.8 ± 0.5 mV and a slope of 18.1 ± 0.4 mV, and inactivate at voltages >+20 mV. As previously observed for mouse EAG and human ERG channels, application of cAMP had no effect on the currents through zebrafish ELK channels [1785]

pH sensitivity of Kv12.1,Kv12.2 and Kv12.3

Whole cell patch clamp recordings made on HEK293 cells transfected with Elk channels hKv12.1, hKv12.2, and hKv12.3 demonstrated that external acidification inhibits their activation. High sensitivity to physiological changes in pH may be a general feature of the EAG superfamily of K+ channels as it was also observed for Kv10.1 and Kv11.1.[1832]

Expression of Kv12.1 in Human

Human KCNH8 is widely expressed in the human central nervous system and appears to overlap the distribution of human KCNH3 and KCNH4, which are also predominantly expressed in the nervous system. [808]

Kv12.1 was also identified in the sympathetic ganglia, testis, brain, colon, lung, uterus, pre-B cell leukemia (ESTs). [790], [809].

Kv12.1 in Rat Brain

Quantification by densitometry showed a very high level of Elk-1 mRNA expression in the granular layer of olfactory bulbs, the pyriform cortex, the dentate gyrus of the hippocampus, and the granular layer of the cerebellum. The labeling was relatively strong in the nucleus accumbens, the caudate–putamen, various nuclei of the thalamus, the CA layers in the hippocampus, the substantia nigra pars compacta, the pedonculopontine nucleus, and throughout the whole cerebral cortex. A low level of expression was observed in the lateral and medial septal nuclei, the substantia nigra pars reticulata (SNr), and the external segment of the globus pallidus (GPe). No significant hybridization signals were obtained in structures corresponding to white matter [1784]

Elk-1 protein detection in striatopallidal and striatonigral axon ter- minals. After unilateral kainic acid lesion of striatal cells, Elk-1 immunodetection was processed on sections corresponding to the external segment of the globus pallidus (GPe) and the substantia nigra pars reticulata (SNr) levels [1784]

Distribution of Kv12.1 in Rat Neurons

Multiple nuclear transcription factors including E-26-like protein 1 (Elk-1) have been found in neuronal dendrites, yet the functional significance of such localization has not yet been explained. Here we use a focal transfection procedure, 'phototransfection', to introduce Elk1 mRNA into specific regions of live, intact primary rat neurons. Introduction and translation of Elk1 mRNA in dendrites produced cell death, whereas introduction and translation of Elk1 mRNA in cell bodies did not produce cell death. Elk-1 translated in dendrites was transported to the nucleus, and cell death depended upon transcription, supporting the dendritic imprinting hypothesis and highlighting the importance of the dendritic environment on protein function [1783]

ELK1 for DNA Binding Modes

Eukaryotic transcription factors are grouped into families and, due to their similar DNA binding domains, often have the potential to bind to the same genomic regions. This can lead to redundancy at the level of DNA binding, and mechanisms are required to generate specific functional outcomes that enable distinct gene expression programmes to be controlled by a particular transcription factor. ELK1 uses different DNA binding modes to regulate functionally distinct classes of target genes [1779]

Prostate

Here, we investigated the expression and function of EPAC in human prostate tissues from patients undergoing radical prostatectomy. EPAC activation may reduce α1-adrenergic prostate contraction in the human prostate, although this effect is masked by cyclooxygenases and β-adrenoceptors. A main EPAC function in the human prostate may be the regulation of the transcription factor Elk1 [1755]

The ETS domain transcription factor ELK1 directs a critical component of growth signaling by the androgen receptor in prostate cancer cells [1758]

Stress stimulates differentiation of ligaments cells via ELK1 pathway

Cyclic tensile stress during physiological occlusal force enhances osteogenic differentiation of human periodontal ligament cells via ERK1/2-Elk1 MAPK pathway [1756]

ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signalling

A characteristic feature of heroin abusers was decreased expression of MOR and extracellular regulated kinase signaling networks, concomitant with dysregulation of the downstream transcription factor ELK1. Striatal ELK1 in heroin abusers associated with the polymorphism rs2075572 in OPRM1 in a genotype dose-dependent manner and correlated with documented history of heroin use, an effect reproduced in an animal model that emphasizes a direct relationship between repeated heroin exposure and ELK1 dysregulation. A central role of ELK1 was evidenced by an unbiased whole transcriptome microarray that revealed ~20% of downregulated genes in human heroin abusers are ELK1 targets. ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1 [1757]

ELK1 controls cell Migration in Breast

Members of the ETS transcription factor family often target the same binding regions and hence have the potential to regulate the same genes and downstream biological processes. The ETS transcription factor ELK1 controls cell migration in breast epithelial cells through targeting a cohort of genes, independently from another family member GABPA, and therefore achieves biological specificity [1759]

Cancer

Ets1 and Elk1 transcription factors regulate cancerous inhibitor of protein phosphatase 2A expression in cervical and endometrial carcinoma cells [1778]

Inflammatory Bowel Diseases

Tumor necrosis factor (TNF-α) is a proinflammatory cytokine that plays a critical role in the pathogenesis of inflammatory bowel disease. TNF-α-induced increase in mouse intestinal permeability requires ERK1/2-dependent activation of Elk-1. These studies provide novel insight into the cellular and molecular processes that regulate the TNF-α-induced increase in intestinal epithelial tight junction permeability [1833]

Coexpression of KCNH8 and KCNH4

Distinct Elk channel subunits can coassemble with each other but that they likely do not coassemble with Eag and Erg family subunits. Coexpression of KCNH8 with dominant-negative KCNH8, KCNH3, and KCNH4 subunits led to suppression of the KCNH8 currents, suggesting that Elk channels can form heteromultimers. [808]

Nutlin-3

Nutlin-3 which occupies the p53 binding pocket in HDM2, has been reported to activate apoptosis through both the transcriptional activity-dependent and -independent programs of p53. Nutlin-3-activated ERK1/2 may stimulate the transcription of BCL2A1 via the activation of ELK1, and BCL2A1 expression may contribute to the inhibitory effect of ERK1/2 on nutlin-3-induced apoptosis, thereby constituting a negative feedback loop of p53-induced apoptosis [1776]

Katanin-p80

Katanin is an ATPase family member protein that participates in microtubule severing. We found that Elk1 activated KATNB1 promoter, and increased both mRNA and protein levels of katanin-p80 in SH-SY5Y cells. On the other hand, KCl treatment increasing SUMOylation decreased KATNB1 promoter activity. Since microtubule severing is an important cellular mechanism of which malfunctions result in serious diseases such as spastic paraplegia, Alzheimer's disease and cell cycle related disorders, identification of KATNB1 transcriptional regulation is crucial in understanding the coordination of microtubule severing activity by different proteins in the cells [1777]

SPG4

Mutations observed in SPG4 gene of hereditary spastic paraplegia patients have been shown to cause reduced spastin levels. In addition to mutations, transcriptional regulation of spastin gene expression may also affect spastin level. It has been identified the binding sites of Elk1 on the SPG4 promoter by EMSA. Over-expression of Elk1 showed that it repressed the SPG4 promoter and also decreased spastin protein level in SHSY-5Y cells [1780]

FADS2

A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1 [1781]

4-AP an Enhancer?

Interestingly, a RELK1 current increase (1.6-fold at 0 mV, n = 7) was observed after bath application of 10 mm 4-AP [809]

PIP2 inhibition of Kv12.1 (Elk1)voltage activation

Phosphatidylinositol 4,5-bisphosphate (PIP2) was shown to inhibit voltage activation of Elk1(KCNH8) but may also stabilize the open state. PIP2 inhibition of voltage activation requires the residues R347 in the S4-S5 linker and R479 near the S6 activation gate.[2085]

Contributors: Rajnish Ranjan, Nitin Khanna, Katherine Johnston