Oestrogen promotes KCNQ1 potassium channel endocytosis and postendocytic trafficking in colonic epithelium

Rapetti-Mauss, Raphaël; O’Mahony, Fiona; Sepúlveda, Francisco V.; Urbach, V.; Harvey, Bill

doi:10.1113/jphysiol.2013.251678

Cited by 39 publications

(43 citation statements)

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“…KCNE1 and KCNE3 (but not KCNE2) are expressed in rat colonic crypts and highly enriched in male versus female rodents; during the estrus cycle, colonic expression of KCNE3 (and colonic partner KCNQ1) fluctuates in a manner consistent with KCNE3 downregulation by estrogen, via PKC phosphorylation of KCNE3 serine 82. In heterologous expression experiments, estrogen inhibited KCNQ1-KCNE3 activity, but not that of KCNQ1-KCNE1 80–82 .…”

Section: Kcne1 and Kcne3 Regulation Of Other Kv α Subunitsmentioning

confidence: 92%

KCNE1 and KCNE3: The yin and yang of voltage-gated K+ channel regulation

Abbott

2016

Gene

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The human KCNE gene family comprises five genes encoding single transmembrane-spanning ion channel regulatory subunits. The primary function of KCNE genes appears to be regulation of voltage-gated potassium (Kv) channels, and the best-understood KCNE complexes are with the KCNQ1 Kv α subunit. Here, we review the often opposite effects of KCNE1 and KCNE3 on Kv channel biology, with an emphasis on regulation of KCNQ1. Slow-activating IKs channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias but by different mechanisms, and each is important for hearing in unique ways. Because of their contrasting effects on KCNQ1 function, KCNE1 and KCNE3 have proved an invaluable tool in the mechanistic understanding of how channel gating can be manipulated, and each may also provide a window into novel insights and new therapeutic opportunities in K+ channel pharmacology. Finally, findings from studies of Kcne1−/− and Kcne3−/− mouse lines serve to illustrate the complexity of KCNE biology and KCNE-linked disease states.

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Section: Kcne1 and Kcne3 Regulation Of Other Kv α Subunitsmentioning

confidence: 92%

KCNE1 and KCNE3: The yin and yang of voltage-gated K+ channel regulation

Abbott

2016

Gene

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“…In normal colonic epithelium, KCNQ1 drives Cl − secretion and generates the resting membrane potential (12,13). Low expression of KCNQ1 has been correlated with CRC development in APC mouse models, but the function of the channels remains unknown (6).…”

Section: Resultsmentioning

confidence: 99%

“…The colon was removed by dissection, and colonic crypts were isolated as previously described in ref. 12.…”

Section: Methodsmentioning

confidence: 99%

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Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation

Rapetti-Mauss

Bustos

Thomas

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The K + channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:β-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/β-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by β-catenin:T-cell factor (TCF)-4. In welldifferentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with β-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of β-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped β-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of β-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/β-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis.T he development of colorectal cancer (CRC) is determined by multiple factors including ion transport (1, 2). During the last 10 years, evidence for the role of K + channels in the development and growth of tumors has greatly expanded. Voltage-gated K + channels (Kv) are involved in the proliferation of many cell types, including intestinal cells. Although the recent literature clearly demonstrates that Kv channels are among the targets of interest in the fight against cancer (3-5), the specific role of each Kv channel in tumorigenesis and the molecular mechanisms involved are unknown. This is notably the case of the KCNQ1 K + channel. The KCNQ1 gene has recently been identified as a tumor suppressor in mouse and human CRC tissues (6). KCNQ1 deficiency in mice caused rectal adenomatous hyperplasia and progression to adenocarcinoma. A loss of imprinting of KCNQ1 has been described in CRC (7). However, the functional and molecular events linking KCNQ1 and CRC progression remain unclear. One obvious pathway, which may interact with KCNQ1, is Wnt/ β-catenin signaling, which plays a key role in driving early embryogenesis, as well as intestinal homeostasis and stem cell renewal in the intestinal mucosa epithelia (8). Deregulation of the β-catenin signaling axis is present in more than 80% of CRC...

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“…In contrast, in epithelial cells of the lower intestine, KCNQ1 interacts with KCNE3, forming a channel that is constitutively active because KCNE3 locks open the KCNQ1 voltage sensor, effectively mimicking membrane depolarization so that the channel can be active at resting membrane potential (46)(47)(48)(49)(50). KCNE3 also confers an additional mode of sensitivity to PKC and is regulated by estrogen (51,52). These properties make KCNQ1-KCNE3 ideal for regulating cAMP-stimulated Cl 2 secretion in the intestine.…”

Section: Discussionmentioning

confidence: 99%

The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury

Zhou

Köhncke

et al. 2019

FASEB j.

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The KCNE2 single transmembrane–spanning voltage‐gated potassium (Kv) channel β subunit is ubiquitously expressed and essential for normal function of a variety of cell types, often via regulation of the KCNQ1 Kv channel. A polymorphism upstream of KCNE2 is associated with reduced lung function in human populations, but the pulmonary consequences of KCNE2 gene disruption are unknown. Here, germline deletion of mouse Kcne2 reduced pulmonary expression of potassium channel α subunits Kcnq1 and Kcnb1 but did not alter expression of other Kcne genes. Kcne2 colocalized and coimmunoprecipitated with Kcnq1 in mouse lungs, suggesting the formation of pulmonary Kcnq1‐Kcne2 potassium channel complexes. Kcne2 deletion reduced blood O2, increased CO2, increased pulmonary apoptosis, and increased inflammatory mediators TNF‐α, IL‐6, and leukocytes in bronchoalveolar lavage (BAL) fluids. Consistent with increased pulmonary vascular leakage, Kcne2 deletion increased plasma, BAL albumin, and the BAL:plasma albumin concentration ratio. Kcne2−/− mouse lungs exhibited baseline induction of the reperfusion injury salvage kinase pathway but were less able to respond via this pathway to imposed pulmonary ischemia/reperfusion injury (IRI). We conclude that KCNE2 regulates KCNQ1 in the lungs and is required for normal lung function and resistance to pulmonary IRI. Our data support a causal relationship between KCNE2 gene disruption and lung dysfunction.—Zhou, L., Köhncke, C., Hu, Z., Roepke, T. K., Abbott, G. W. The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury. FASEB J. 33, 9762–9774 (2019). http://www.fasebj.org

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Oestrogen promotes KCNQ1 potassium channel endocytosis and postendocytic trafficking in colonic epithelium

Cited by 39 publications

References 50 publications

KCNE1 and KCNE3: The yin and yang of voltage-gated K+ channel regulation

KCNE1 and KCNE3: The yin and yang of voltage-gated K+ channel regulation

Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation

The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury

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