A5037554008- Ion channel regulation and function
- Cystic Fibrosis Research Advances
- Ion Transport and Channel Regulation
- Neonatal Respiratory Health Research
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neuropharmacology Research
- Asthma and respiratory diseases
- Ion Channels and Receptors
- Genetic and Kidney Cyst Diseases
- Cancer Research and Treatments
- Cancer Cells and Metastasis
- Renal and related cancers
- Neuroscience of respiration and sleep
- Adenosine and Purinergic Signaling
- Erythrocyte Function and Pathophysiology
- Biomedical Research and Pathophysiology
- Cellular transport and secretion
- Signaling Pathways in Disease
- Pancreatic function and diabetes
- Respiratory and Cough-Related Research
- CRISPR and Genetic Engineering
- Tracheal and airway disorders
- Receptor Mechanisms and Signaling
- Metabolism, Diabetes, and Cancer
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
University of Regensburg
2016-2025
Magee-Womens Research Institute
2012
UPMC Hillman Cancer Center
2012
University Medical Center
2012
University of Pittsburgh Medical Center
2012
Duke University Hospital
2012
Duke Medical Center
2012
University of Florida
2012
University of Pittsburgh
2012
VA Pittsburgh Healthcare System
2012
Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement human tumorigenesis not previously studied. Here, we show a functional role for tumor growth. We found overexpression 80% head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival patients SCCHN. significantly promoted anchorage-independent growth vitro, loss resulted...
Molecular identification of the Ca(2+)-dependent chloride channel TMEM16A (ANO1) provided a fundamental step in understanding Cl(-) secretion epithelia. is an intrinsic constituent channels cultured epithelia and may control salivary output, but its physiological role native epithelial tissues remains largely obscure. Here, we demonstrate that activated by agonists missing mice lacking expression TMEM16A. transport was or reduced isolated tracheal colonic epithelia, as well hepatocytes...
The calcium-activated chloride channel anoctamin1 (ANO1; TMEM16A) is fundamental for the function of epithelial organs. Mice lacking ANO1 expression exhibit transport defects and a pathology similar to cystic fibrosis. They also show general defect electrolyte transport. Here we analyzed all ten members (ANO1-ANO10) in broad range murine tissues detected predominant ANO1, 6, 7, 8, 9, 10 tissues, while ANO2, 3, 4, 5 are common neuronal muscle tissues. When expressed Fisher Rat Thyroid (FTR)...
Cystic fibrosis (CF) airway cells, besides their well-known defect in cAMP-dependent Cl- conductance, are characterized by an enhanced Na+ conductance. In this study we have examined the conductance human respiratory tract measuring transepithelial voltage and resistance (Vte, Rte) assessing membrane voltages (Vm) of freshly isolated epithelial cells from CF non-CF patients. Basal amiloride inhibitable (10 micromol/liter) equivalent short circuit current (Isc = Vte/Rte) was significantly...
Anoctamin 1 (Ano1; TMEM16A) and anoctamin 2 (Ano2; TMEM16B) are novel Cl− channels transiently activated by increase in intracellular Ca2+. These essential for epithelial secretion, smooth muscle peristalsis olfactory signal transduction. They central to inherited diseases cancer can act as heat sensors. Surprisingly, another member of this protein-family, Ano6, operates a Ca2+ phospholipid scramblase, while others were reported proteins. It is therefore unclear whether anoctamins constitute...
All vertebrate cells regulate their cell volume by activating chloride channels of unknown molecular identity, thereby regulatory decrease. We show that the Ca(2+)-activated Cl(-) channel TMEM16A together with other TMEM16 proteins are activated swelling through an autocrine mechanism involves ATP release and binding to purinergic P2Y(2) receptors. increase in intracellular Ca(2+) a Ca(2+)-independent engaging extracellular-regulated protein kinases (ERK1/2). The ability epithelial activate...
Outwardly rectifying chloride channels (ORCC, ICOR) of intermediate single-channel conductance around 50 pS, are ubiquitously expressed, but have remained a mystery since their description more than 25 y ago. These been shown to be activated on membrane excision and depolarization the voltage by cAMP in presence cystic fibrosis transmembrane regulator. We show that anoctamin 6 (Ano6), member recently identified family putative Cl(-) channels, is crucial component ORCC whole-cell currents...
Head and neck squamous cell carcinoma (HNSCC) has the potential for early metastasis is associated with poor survival. Ano1 (Dog1) an established sensitive marker diagnosis of gastrointestinal stromal tumors (GIST) recently been identified as a Ca(2+) activated Cl(-) channel. Although ANO1 gene located on 11q13 locus, region which known to be amplified in different types human carcinomas, detailed analysis amplification expression HNSCC not performed. It thus still unclear how contributes...
TMEM16A (anoctamin 1, Ano1), a member of family 10 homologous proteins, has been shown to form an essential component Ca2+-activated CU channels. TMEM16A-null mice exhibit severe defects in epithelial transport along with tracheomalacia and death within 1 mo after birth. Despite its outstanding physiological significance, the mechanisms for activation remain obscure. is activated on increase intracellular Ca2+, but it unclear whether Ca2+ binds directly channel or additional components are...
Purinergic P2X7 receptors (P2X7R) are fundamental to innate immune response. In macrophages, transient stimulation of P2X7R activates several transport mechanisms and induces the scrambling phospholipids with subsequent membrane blebbing apoptosis. These processes support phagocytosis killing phagocytosed bacteria. Here we demonstrate that anoctamin 6 (ANO6, TMEM16F), a protein functions as Ca(2+) dependent phospholipid scramblase Ca(2+)-activated Cl(-) channel. Inhibition or knockdown ANO6...
Significance First insight into the molecular identity of volume-regulated anion channel (VRAC) emerged only recently by demonstrating a role for leucine-rich repeats containing 8A (LRRC8A) in activity. Our results now expand on VRAC biology, suggesting model where subunit composition is cell type- or tissue-specific rather than single ubiquitous formed solely LRRC8A. Here, we show that bestrophin 1 (BEST1), but not LRCC8A, crucial volume regulation retinal pigment epithelium (RPE) cells...
Abstract Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is the secretory chloride/bicarbonate channel in airways and intestine that activated through ATP binding phosphorylation by protein kinase A, but fails to operate cystic fibrosis (CF). TMEM16A (also known as anoctamin 1, ANO1) thought function Ca 2+ chloride independent of CFTR. Here we report tissue specific knockout gene mouse not only eliminates -activated Cl − currents, unexpectedly also abrogates CFTR-mediated...
The Ca2+-activated Cl‒ channel TMEM16A [anoctamin (ANO)1] is homologous to yeast Ist2 and has been shown tether the cortical endoplasmic reticulum (ER) plasma membrane. We therefore examined whether ANO1 other members of ANO family affect intracellular Ca2+ ([Ca2+]i) signals. It that expression augments store release upon stimulation GPCRs, whereas knockdown ANO1, or lack Ano1 in Ano1‒/‒ animals, as an earlier report, inhibits release. ANO6, −10 show similar effects, ANO4, −8, −9 attenuate...
Transmembrane member 16A (TMEM16A) is the Ca2+-activated chloride channel in airways and intestine. It has been associated with goblet cell metaplasia, as expression of TMEM16A strongly up-regulated cystic fibrosis asthma during mucus hypersecretion. However, possible role for production or secretion remains obscure, whether controls function intestinal cells entirely unknown. Basal lungs occurs through low levels ATP airway surface liquid. Here, we report first time that essential basal...
Significance Statement The chloride channels cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) drive cyst enlargement in polycystic kidney disease (PKD), ultimately leading to failure. mechanisms for channel activation, however, are poorly understood. authors show the first time that peroxidation of plasma membrane phospholipids activates renal TMEM16A; this facilitates calcium signaling activation calcium-sensitive adenylate cyclase ADCY1, which further...
Inflammatory airway diseases, such as asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD), are characterized by mucus hypersecretion plugging. In both CF enhanced expression of the Ca2+-activated Cl– channel TMEM16A is detected in mucus-producing club/goblet cells smooth muscle. contributes to bronchoconstriction, which inhibited blockers TMEM16A, niflumic acid. Here we demonstrate that FDA-approved drug niclosamide, a potent inhibitor identified high-throughput...
Abstract Purpose: Voltage-gated Kv potassium channels, like ether a go-go (EAG) have been recognized for their oncogenic potential in breast cancer and other malignant tumors. Experimental Design: We examined the molecular functional expression of channels human colonic cancers colon mice treated with chemical carcinogens dimethylhydrazine N-methyl-N-nitrosourea. The data were compared results from control animals chemically induced DSS colitis. Results: Electrogenic salt transport by...
Cystic fibrosis is characterized by an impaired cyclic adenosine 3,5‐monophosphate (cAMP) activated Cl − conductance in parallel with enhanced amiloride sensitive Na + (ENaC) of the respiratory epithelium. Very recently, acute downregulation ENaC cystic transmembrane regulator (CFTR) was demonstrated several studies. The mechanism, however, which CFTR exerts its inhibitory effect on remains obscure. We demonstrate that cytosolic domains human are sufficient to induce inhibition rat...
Stimulation of purinergic receptors inhibits amiloride-sensitive Na+ transport in epithelial tissues by an unknown mechanism. Because previous studies excluded the role intracellular Ca2+ or protein kinase C, we examined whether regulation absorption occurs via hydrolysis phospholipid such as phosphatidylinositol-bisphosphates (PIP2). Inhibition short-circuit currents (Isc-Amil) adenine 5'-triphosphate (ATP) native tracheal epithelia and M1 collecting duct cells was suppressed binding...