Structure and Function of TMEM16 Proteins (Anoctamins)

2014 ◽  
Vol 94 (2) ◽  
pp. 419-459 ◽  
Author(s):  
Nicoletta Pedemonte ◽  
Luis J. V. Galietta
Keyword(s):  
Ion Transport ◽  
Ion Channel ◽  
Neuronal Excitability ◽  
Genetic Diseases ◽  
Smooth Muscle Contraction ◽  
Dual Function ◽  
Anoctamin 1 ◽  
Genetic Ablation ◽  
Cell Functions ◽  
Outer Leaflet

TMEM16 proteins, also known as anoctamins, are involved in a variety of functions that include ion transport, phospholipid scrambling, and regulation of other membrane proteins. The first two members of the family, TMEM16A (anoctamin-1, ANO1) and TMEM16B (anoctamin-2, ANO2), function as Ca2+-activated Cl−channels (CaCCs), a type of ion channel that plays important functions such as transepithelial ion transport, smooth muscle contraction, olfaction, phototransduction, nociception, and control of neuronal excitability. Genetic ablation of TMEM16A in mice causes impairment of epithelial Cl−secretion, tracheal abnormalities, and block of gastrointestinal peristalsis. TMEM16A is directly regulated by cytosolic Ca2+as well as indirectly by its interaction with calmodulin. Other members of the anoctamin family, such as TMEM16C, TMEM16D, TMEM16F, TMEM16G, and TMEM16J, may work as phospholipid scramblases and/or ion channels. In particular, TMEM16F (ANO6) is a major contributor to the process of phosphatidylserine translocation from the inner to the outer leaflet of the plasma membrane. Intriguingly, TMEM16F is also associated with the appearance of anion/cation channels activated by very high Ca2+concentrations. Furthermore, a TMEM16 protein expressed in Aspergillus fumigatus displays both ion channel and lipid scramblase activity. This finding suggests that dual function is an ancestral characteristic of TMEM16 proteins and that some members, such as TMEM16A and TMEM16B, have evolved to a pure channel function. Mutations in anoctamin genes ( ANO3, ANO5, ANO6, and ANO10) cause various genetic diseases. These diseases suggest the involvement of anoctamins in a variety of cell functions whose link with ion transport and/or lipid scrambling needs to be clarified.

scholarly journals Arkadia-SKI/SnoN signaling differentially regulates TGF-β–induced iTreg and Th17 cell differentiation

2021 ◽  
Vol 218 (11) ◽  
Author(s):  
Hao Xu ◽  
Lin Wu ◽  
Henry H. Nguyen ◽  
Kailin R. Mesa ◽  
Varsha Raghavan ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Treg Cell ◽  
Th17 Cell ◽  
Mucosal Inflammation ◽  
Genetic Ablation ◽  
Downstream Signaling ◽  
Cell Functions ◽  
Itreg Cell

TGF-β signaling is fundamental for both Th17 and regulatory T (Treg) cell differentiation. However, these cells differ in requirements for downstream signaling components, such as SMAD effectors. To further characterize mechanisms that distinguish TGF-β signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-β signaling during development. Inactivation of Arkadia in CD4+ T cells resulted in impaired Treg cell differentiation in vitro and loss of RORγt+FOXP3+ iTreg cells in the intestinal lamina propria, which increased susceptibility to microbiota-induced mucosal inflammation. In contrast, Arkadia was dispensable for Th17 cell responses. Furthermore, genetic ablation of two Arkadia substrates, the transcriptional corepressors SKI and SnoN, rescued Arkadia-deficient iTreg cell differentiation both in vitro and in vivo. These results reveal distinct TGF-β signaling modules governing Th17 and iTreg cell differentiation programs that could be targeted to selectively modulate T cell functions.

scholarly journals Cancer Exacerbates Chemotherapy Induced Sensory Neuropathy

2019 ◽  
Author(s):  
Stephen N. Housley ◽  
Paul Nardelli ◽  
Dario Carrasco ◽  
Emily Pfahl ◽  
Lilya Matyunina ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Ion Channel ◽  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Inflammatory Responses ◽  
Transcriptional Profiling ◽  
Sensory Neuropathy ◽  
Potential Contributor ◽  
Sensory Encoding ◽  
Linear Interactions

AbstractFor the constellation of neurological disorders known as chemotherapy induced peripheral neuropathy, mechanistic understanding, and treatment remain deficient. Here we present the first evidence in preclinical investigation of rats that chronic sensory neuropathy depends on non-linear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as a potential contributor to sensory neuron dysfunction. These original findings identify novel contributors to peripheral neuropathy, and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer.

scholarly journals Therapeutic Inhibition of Acid Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury

Circulation ◽  
2021 ◽  
Author(s):  
Meredith A. Redd ◽  
Sarah E. Scheuer ◽  
Natalie J. Saez ◽  
Yusuke Yoshikawa ◽  
Han Sheng Chiu ◽  
...  
Keyword(s):  
Ion Channel ◽  
Reperfusion Injury ◽  
Electromechanical Coupling ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Genetic Ablation ◽  
Organ Level

Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the build-up of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6.0-6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly impacts cardiac function. Methods: We used genetic and pharmacological methods to investigate the role of acid sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole organ level. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and post-conditioning therapeutic agents. Results: Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using hiPSC-CMs in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacological inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction (MI) and two models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as pre- or post-conditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no impact on cardiac ion channels regulating baseline electromechanical coupling and physiological performance. Conclusions: Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

ChemInform Abstract: Biomimetic Ion Transport: A Functional Model of a Unimolecular Ion Channel.

ChemInform ◽  
1989 ◽  
Vol 20 (18) ◽  
Author(s):  
V. E. CARMICHAEL ◽  
P. J. DUTTON ◽  
T. M. FYLES ◽  
T. D. JAMES ◽  
J. A. SWAN ◽  
...  
Keyword(s):  
Ion Transport ◽  
Ion Channel ◽  
Functional Model

Endogenous ion channel complexes: the NMDA receptor

2011 ◽  
Vol 39 (3) ◽  
pp. 707-718 ◽  
Author(s):  
René A.W. Frank
Keyword(s):  
Nmda Receptor ◽  
Ion Channel ◽  
Present Article ◽  
Neuronal Excitability ◽  
Structure And Function ◽  
Current Understanding ◽  
Ionotropic Receptors ◽  
Receptor Complexes ◽  
Aspartate Receptor ◽  
And Function

Ionotropic receptors, including the NMDAR (N-methyl-D-aspartate receptor) mediate fast neurotransmission, neurodevelopment, neuronal excitability and learning. In the present article, the structure and function of the NMDAR is reviewed with the aim to condense our current understanding and highlight frontiers where important questions regarding the biology of this receptor remain unanswered. In the second part of the present review, new biochemical and genetic approaches for the investigation of ion channel receptor complexes will be discussed.

scholarly journals TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation

2017 ◽  
Vol 312 (5) ◽  
pp. C562-C572 ◽  
Author(s):  
Shweta Sharma ◽  
Rishov Goswami ◽  
Michael Merth ◽  
Jonathan Cohen ◽  
Kai Y. Lei ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Dermal Fibroblasts ◽  
Transient Receptor Potential Vanilloid ◽  
Myofibroblast Differentiation ◽  
Dependent Manner ◽  
Matrix Stiffness ◽  
Functional Link ◽  
Genetic Ablation

Scleroderma is a multisystem fibroproliferative disease with no effective medical treatment. Myofibroblasts are critical to the fibrogenic tissue repair process in the skin and many internal organs. Emerging data support a role for both matrix stiffness, and transforming growth factor β1 (TGFβ1), in myofibroblast differentiation. Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel activated by both mechanical and biochemical stimuli. The objective of this study was to determine the role of TRPV4 in TGFβ1- and matrix stiffness-induced differentiation of dermal fibroblasts. We found that TRPV4 channels are expressed and functional in both human (HDF) and mouse (MDF) dermal fibroblasts. TRPV4 activity (agonist-induced Ca2+ influx) was induced by both matrix stiffness and TGFβ1 in dermal fibroblasts. TGFβ1 induced expression of TRPV4 proteins in a dose-dependent manner. Genetic ablation or pharmacological antagonism of TRPV4 channel abrogated Ca2+ influx and both TGFβ1-induced and matrix stiffness-induced myofibroblast differentiation as assessed by 1) α-smooth muscle actin expression/incorporation into stress fibers, 2) generation of polymerized actin, and 3) expression of collagen-1. We found that TRPV4 inhibition abrogated TGFβ1-induced activation of AKT but not of Smad2/3, suggesting that the mechanism by which profibrotic TGFβ1 signaling in dermal fibroblasts is modified by TRPV4 may be through non-Smad pathways. Altogether, these data identify a novel reciprocal functional link between TRPV4 activation and TGFβ1 signals regulating dermal myofibroblast differentiation. These findings suggest that therapeutic inhibition of TRPV4 activity may provide a targeted approach to the treatment of scleroderma.

Inhibitory Effects of Thiopental, Ketamine, and Propofol on Voltage-dependent Calcium sup 2+ Channels in Porcine Tracheal Smooth Muscle Cells

1995 ◽  
Vol 83 (6) ◽  
pp. 1274-1282 ◽  
Author(s):  
Michiaki Yamakage ◽  
Carol A. Hirshman ◽  
Thomas L. Croxton
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Ion Channel ◽  
Muscle Contraction ◽  
Airway Smooth Muscle ◽  
Smooth Muscle Contraction ◽  
Inhibitory Effects ◽  
Intravenous Anesthetics ◽  
Anesthetic Agents ◽  
Voltage Dependent

Abstract Background Intravenously administered anesthetics directly inhibit airway smooth muscle contraction. Because many anesthetic agents affect membrane ion channel function and sustained contraction of airway smooth muscle requires the influx of Calcium2+ through voltage-dependent Calcium2+ channels, it was hypothesized that intravenous anesthetics inhibit airway smooth muscle voltage-dependent Calcium2+ channels.

scholarly journals Genetic ablation of androgen receptor signaling in fetal Leydig cell lineage affects Leydig cell functions in adult testis

2015 ◽  
Vol 29 (6) ◽  
pp. 2327-2337 ◽  
Author(s):  
Elena M. Kaftanovskaya ◽  
Carolina Lopez ◽  
Lydia Ferguson ◽  
Courtney Myhr ◽  
Alexander I. Agoulnik
Keyword(s):  
Androgen Receptor ◽  
Leydig Cell ◽  
Cell Lineage ◽  
Receptor Signaling ◽  
Androgen Receptor Signaling ◽  
Adult Testis ◽  
Genetic Ablation ◽  
Cell Functions
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