Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology

Wu, Wei; Sanguinetti, Michael C.

doi:10.1016/j.ccep.2016.01.002

Cited by 34 publications

(29 citation statements)

References 98 publications

(96 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the heart the Kv7.1-KCNE1 complex mediates the I κs current of the cardiac action potential [103–105]. Numerous loss-of-function mutations in Kv7.1 are known to cause cardiac long-QT syndrome (LQTS) type 1 characterized by a prolonged QT interval that predisposes an individual for certain ventricular arrhythmias, which can result in syncope or sudden death [106].…”

Section: Kv7 Channels and Diseasementioning

confidence: 99%

“…In addition to the need to develop a complete understanding of how PIP 2 modulates the function of the naked Kv7 channel, it has also been established that the capacity of PIP 2 to enhance Kv7.1 channel function is enhanced 100-fold by the presence of KCNE1, which itself modulates Kv7.1 channel function in a way that is both complex and responsible for formation of the I Ks current of the cardiac action potential [103–105]. This suggests that KCNE1 and PIP 2 both bind to the channel and act synergistically to establish the function of Kv7.1 in some physiological settings.…”

Section: Modulation Of Kv7 Channels By Specific Binding Of Pip2mentioning

confidence: 99%

See 1 more Smart Citation

Regulation of KCNQ/Kv7 family voltage-gated K + channels by lipids

Taylor

Sanders

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

Many years of studies have established that lipids can impact membrane protein structure and function through bulk membrane effects, by direct but transient annular interactions with the bilayer-exposed surface of the protein transmembrane domains, and by specific binding to protein sites. Here, we focus on how phosphatidylinositol 4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) impact ion channel function and how the structural details of the interactions of these lipids with ion channels are beginning to emerge. We focus on the Kv7 (KCNQ) sub-family of voltage-gated K+ channels, which are regulated by both PIP2 and PUFAs and play a variety of important roles in human health and disease.

show abstract

Section: Kv7 Channels and Diseasementioning

confidence: 99%

Section: Modulation Of Kv7 Channels By Specific Binding Of Pip2mentioning

confidence: 99%

Regulation of KCNQ/Kv7 family voltage-gated K + channels by lipids

Taylor

Sanders

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

show abstract

“…In contrast, Eag1 is overexpressed in many cancer cell lines and human tumors, including those from the liver, cervix, lung, breast, and colon [11,13,[15][16][17][18][19]. Interestingly, the human Eag-related channel (Herg1), which is very relevant for cardiac repolarization [20], has been found to be overexpressed in retinoblastoma samples from patients that did not benefit from conservative treatment, namely chemotherapy followed by cryotherapy and/or laser treatment [21]. Eag1 has also been proposed as a novel anti-cancer target because the inhibition of either its gene expression or channel activity decreases the tumor cell proliferation in vitro and in vivo [22].…”

Section: Introductionmentioning

confidence: 99%

Eag1 Gene and Protein Expression in Human Retinoblastoma Tumors and its Regulation by pRb in HeLa Cells

Chávez-López

Zúñiga-García

Castro-Magdonel

et al. 2020

Genes

View full text Add to dashboard Cite

Retinoblastoma is the most common pediatric intraocular malignant tumor. Unfortunately, low cure rates and low life expectancy are observed in low-income countries. Thus, alternative therapies are needed for patients who do not respond to current treatments or those with advanced cases of the disease. Ether à-go-go-1 (Eag1) is a voltage-gated potassium channel involved in cancer. Eag1 expression is upregulated by the human papilloma virus (HPV) oncogene E7, suggesting that retinoblastoma protein (pRb) may regulate Eag1. Astemizole is an antihistamine that is suggested to be repurposed for cancer treatment; it targets proteins implicated in cancer, including histamine receptors, ATP binding cassette transporters, and Eag channels. Here, we investigated Eag1 regulation using pRb and Eag1 expression in human retinoblastoma. The effect of astemizole on the cell proliferation of primary human retinoblastoma cultures was also studied. HeLa cervical cancer cells (HPV-positive and expressing Eag1) were transfected with RB1. Eag1 mRNA expression was studied using qPCR, and protein expression was assessed using western blotting and immunochemistry. Cell proliferation was evaluated with an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RB1 transfection down-regulated Eag1 mRNA and protein expression. The human retinoblastoma samples displayed heterogeneous Eag1 mRNA and protein expression. Astemizole decreased cell proliferation in primary retinoblastoma cultures. Our results suggest that Eag1 mRNA and protein expression was regulated by pRb in vitro, and that human retinoblastoma tissues had heterogeneous Eag1 mRNA and protein expression. Furthermore, our results propose that the multitarget drug astemizole may have clinical relevance in patients with retinoblastoma, for instance, in those who do not respond to current treatments.

show abstract

“…The KCNQ1 (K V 7.1) voltage-gated potassium channel plays a critical role in the cardiac action potential (1-3). Inherited missense mutations in KCNQ1 encode amino acid changes in the protein that can trigger either loss of channel function (LOF) or aberrant gain-of-function (GOF) (4)(5)(6)(7). LOF mutations cause type 1 long QT syndrome (LQTS) cardiac arrhythmia, a cause of sudden death.…”

Section: Introductonmentioning

confidence: 99%

Disease-Linked Super-Trafficking of a Mutant Potassium Channel

Huang

Chamness

Vanoye³

et al. 2020

Preprint

View full text Add to dashboard Cite

Gain-of-function (GOF) mutations in the KCNQ1 voltage-gated potassium channel can induce cardiac arrhythmia. We tested whether any of the known GOF disease mutations in KCNQ1 act by increasing the amount of KCNQ1 that reaches the cell surface—“super-trafficking”. We found that levels of R231C KCNQ1 in the plasma membrane are 5-fold higher than wild type KCNQ1. This arises from both enhanced translocon-mediated membrane integration of the S4 voltage-sensor helix and an energetic linkage of C231 with the V129 and F166 side chains. Whole-cell electrophysiology recordings confirmed that R231C KCNQ1 in complex with KCNE1 is constitutively active, but also revealed the single channel activity of this mutant to be only 20% that of WT. The GOF phenotype associated with R231C therefore reflects the net effects of super-trafficking, reduced single channel activity, and constitutive channel activation. These investigations document membrane protein super-trafficking as a contributing mechanism to human disease.

show abstract

Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology

Cited by 34 publications

References 98 publications

Regulation of KCNQ/Kv7 family voltage-gated K + channels by lipids

Regulation of KCNQ/Kv7 family voltage-gated K + channels by lipids

Eag1 Gene and Protein Expression in Human Retinoblastoma Tumors and its Regulation by pRb in HeLa Cells

Disease-Linked Super-Trafficking of a Mutant Potassium Channel

Contact Info

Product

Resources

About