A new regulation mechanism for KCNN4, the Ca-dependent K channel, by molecular interactions with the Capump PMCA4b.

KCNN4, a Ca-activated K channel, is involved in various physiological and pathological processes. It is essential for epithelial transport, immune system, and other physiological mechanisms, but its activation is also involved in cancer pathophysiology as well as red blood cell (RBC) disorders. The activation of KCNN4 in RBC leads to loss of KCl and water, a mechanism known as the "Gardos effect" described 70 years ago.

A network embedding approach to identify active modules in biological interaction networks.

The identification of condition-specific gene sets from transcriptomic experiments is important to reveal regulatory and signaling mechanisms associated with a given cellular response. Statistical methods of differential expression analysis, designed to assess individual gene variations, have trouble highlighting modules of small varying genes whose interaction is essential to characterize phenotypic changes. To identify these highly informative gene modules, several methods have been proposed in recent years, but they have many limitations that make them of little use to biologists.

SK2 channels set a signalling hub bolstering CAF-triggered tumourigenic processes in pancreatic cancer.

Objective: Intercellular communication within pancreatic ductal adenocarcinoma (PDAC) dramatically contributes to metastatic processes. The underlying mechanisms are poorly understood, resulting in a lack of targeted therapy to counteract stromal-induced cancer cell aggressiveness. Here, we investigated whether ion channels, which remain understudied in cancer biology, contribute to intercellular communication in PDAC.

New KCNN4 Variants Associated With Anemia: Stomatocytosis Without Erythrocyte Dehydration.

The K channel activated by the Ca, KCNN4, has been shown to contribute to red blood cell dehydration in the rare hereditary hemolytic anemia, the dehydrated hereditary stomatocytosis. We report two mutations on , We reported two mutations on , V222L and H340N, characterized at the molecular, cellular and clinical levels. Whereas both mutations were shown to increase the calcium sensitivity of the K channel, leading to channel opening for lower calcium concentrations compared to WT KCNN4 channel, there was no obvious red blood cell dehydration in patients carrying one or the other mutation.

Hereditary Xerocytosis: Differential Behavior of PIEZO1 Mutations in the N-Terminal Extracellular Domain Between Red Blood Cells and HEK Cells.

Hereditary Xerocytosis, a rare hemolytic anemia, is due to gain of function mutations in PIEZO1, a non-selective cation channel activated by mechanical stress. How these PIEZO1 mutations impair channel function and alter red blood cell (RBC) physiology, is not completely understood. Here, we report the characterization of mutations in the N-terminal part of the protein (V598M, F681S and the double mutation G782S/R808Q), a part of the channel that was subject of many investigations to decipher its role in channel gating.

Interplay Between Ion Channels and the Wnt/β-Catenin Signaling Pathway in Cancers.

Increasing evidence point out the important roles of ion channels in the physiopathology of cancers, so that these proteins are now considered as potential new therapeutic targets and biomarkers in this disease. Indeed, ion channels have been largely described to participate in many hallmarks of cancers such as migration, invasion, proliferation, angiogenesis, and resistance to apoptosis. At the molecular level, the development of cancers is characterised by alterations in transduction pathways that control cell behaviors.

Potassium and Calcium Channel Complexes as Novel Targets for Cancer Research.

The intracellular Ca concentration is mainly controlled by Ca channels. These channels form complexes with K channels, which function to amplify Ca flux. In cancer cells, voltage-gated/voltage-dependent Ca channels and non-voltage-gated/voltage-independent Ca channels have been reported to interact with K channels such as Ca-activated K channels and voltage-gated K channels.

Primary red cell hydration disorders: Pathogenesis and diagnosis.

Hydration status is critical for erythrocyte survival and is mainly determined by intracellular cation content. Active pumps, passive transporters, and ion channels are the key components of volume homeostasis, whereas water passively fits ionic movements. Whenever cation content increases, erythrocyte swells, whereas it shrinks when cation content decreases.

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

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.

Sigma 1 Receptor and Ion Channel Dynamics in Cancer.

SigmaR1 is a multitasking chaperone protein which has mainly been studied in CNS physiological and pathophysiological processes such as pain, memory, neurodegenerative diseases (amyotrophic lateral sclerosis , Parkinson's and Alzheimer's diseases, retinal neurodegeneration ), stroke and addiction . Strikingly, G-protein and ion channels are the main client protein fami lies of this atypical chaperone and the recent advances that have been performed for the last 10 years demonstrate that SigmaR1 is principally activated following tissue injury and disease development to promote cell survival. In this chapter, we synthesize the data enhancing our comprehension of the interaction between SigmaR1 and ion channels and the unexpected consequences of such functional coupling in cancer development.

The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca homeostasis.

The remodeling of calcium homeostasis contributes to the cancer hallmarks and the molecular mechanisms involved in calcium channel regulation in tumors remain to be characterized. Here, we report that SigmaR1, a stress-activated chaperone, is required to increase calcium influx by triggering the coupling between SK3, a Ca-activated K channel (KCNN3) and the voltage-independent calcium channel Orai1. We show that SigmaR1 physically binds SK3 in BC cells.

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness.

The sigma 1 receptor (Sig1R) is a stress-activated chaperone that regulates ion channels and is associated with pathologic conditions, such as stroke, neurodegenerative diseases, and addiction. Aberrant expression levels of ion channels and Sig1R have been detected in tumors and cancer cells, such as myeloid leukemia and colorectal cancer, but the link between ion channel regulation and Sig1R overexpression during malignancy has not been established. In this study, we found that Sig1R dynamically controls the membrane expression of the human voltage-dependent K(+) channel human ether-à-go-go-related gene (hERG) in myeloid leukemia and colorectal cancer cell lines.

A mutation in the Gardos channel is associated with hereditary xerocytosis.

The Gardos channel is a Ca(2+)-sensitive, intermediate conductance, potassium selective channel expressed in several tissues including erythrocytes and pancreas. In normal erythrocytes, it is involved in cell volume modification. Here, we report the identification of a dominantly inherited mutation in the Gardos channel in 2 unrelated families and its association with chronic hemolysis and dehydrated cells, also referred to as hereditary xerocytosis (HX).

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

The cAMP-regulated potassium channel KCNQ1:KCNE3 plays an essential role in transepithelial Cl(-) secretion. Recycling of K(+) across the basolateral membrane provides the driving force necessary to maintain apical Cl(-) secretion. The steroid hormone oestrogen (17β-oestradiol; E2), produces a female-specific antisecretory response in rat distal colon through the inhibition of the KCNQ1:KCNE3 channel.

Estrogen regulation of epithelial ion transport: Implications in health and disease.

Estrogen, 17β-estradiol (E2), has been shown to modulate the activity of ion channels in a diverse range of epithelial tissues. The channel activation or inhibition responses to E2 are often rapid, occurring in seconds to minutes, independent of protein synthesis and gene transcription ('non-genomic' response). These rapid effects of E2 require activation of specific protein kinases or changes in intracellular calcium and pH which in turn modulate the conductance, open probability or number of channels in the plasmamembrane.

Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K⁺ channels.

The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation, some time-dependent activation at very positive potentials, a linear current-voltage relationship and a 10-fold higher sensitivity to chromanol 293B. KCNQ1:KCNE3 channels are expressed in colonic crypts and mediate basolateral K(+) recycling required for Cl(-) secretion.

Sig1R protein regulates hERG channel expression through a post-translational mechanism in leukemic cells.

Sig1R (Sigma-1receptor) is a 25-kDa protein structurally unrelated to other mammalian proteins. Sig1R is present in brain, liver, and heart and is overexpressed in cancer cells. Studies using exogenous sigma ligands have shown that Sig1R interacts with a variety of ion channels, but its intrinsic function and mechanism of action remain unclear.