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Anoctamin-1, a Cloned Ca^(2+)-activated Chloride Channel and Its Physiological Implication
Oh, Uhtaek 이화여자대학교 세포신호전달연구센터 2009 고사리 세포신호전달 심포지움 Vol. No.11
Chloride channels mediate fundamental physiological functions in our body. They are important for mediating transports of electrolytes and water across the epithelium, stabilization of membrane potentials, regulation of cell volume, and controlling intracellular pH. Among many different types of Cl- channels, one group of Cl- channels are important in mediating critical functions. This channel is a Ca^(2+)-activated chloride channels(CaCCs), which is activated by intracellular Ca^(2+). CaCCs is known to mediate the apical movement of Cl^(-) in secretory epithelia in salivary glands, airways, and kidneys. CaCCs are also known to control the excitability of muscles and neurons. Moreover, CaCCs also regulate sensory transduction in retina and other sensory organs. CaCC are initiated by stimulation stimulation of G-protein coupled receptors. Thus, many bioactive ligands such as acetylcholine, ATP, endothelin-1, angiotensin II, and histamine are known to activate CaCCs for initiating their own physiological functions such as salivation, airway clearance, and smooth muscle contraction. Despite their significance in mediating body functions, a molecular species that defines endogenous CaCCs has not been disclosed. In our recent report, we showed that TMEM16A is a CaCC. TMEM16A retains the hall marks of characteristic pharmacological and biophysical properties of endogenous CaCCs. block by Cl^(-) channel blockers, small single channel conductance, a voltage-dependent Ca^(2+) sensitivity, and anion permeability sequence, I^(-) > Br^(-) > Cl^(-) > F^(-). TMEM16A is activated by intracellular Ca^(2+) and Ca^(2+)-mobilizing stimuli when expressed in oocytes or in mammalian cells. Because it has eight putative transmembrane domains and an anion channel, we changed its name as anoctamin 1(ANO1). Anoctamin 1 has 9 additional paralogs comprising superfamily and defines a novel family of ionic channels because of its unique topology. Mutational studies also predicted a putative pore region of the channel. Furthermore, ANO1 is expressed in epithelia of salivary glands, pancreas, kidney, pulmonary airways, the retina, and sensory neurons where CaCC currents were found. Together, we conclude that ANO1 is a candidate Ca^(2+)-activated chloride channel that mediates diverse physiological processes.
Endogenous Lipid-derived Ligands for Sensory TRP Ion Channels and Their Pain Modulation
방상수,유성재,Uhtaek Oh,황선욱 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.10
Environmental or internal noxious stimuli excite the primary sensory nerves in our body. The sensory nerves relay these signals by electrical discharges to the brain, leading to pain perception. Six transient receptor potential (TRP) ion channels are expressed in the sensory nerve terminals and play a crucial role in sensing diverse noxious stimuli. Cation influx through activated TRP ion channels depolarizes the plasma membrane, resulting in neuronal excitation and pain. Natural and synthetic compounds have been found to act on these sensory TRP channels to alter the nociception. Evidence is growing that lipidergic substances are also cable of modifying TRP ion channel activity by direct binding. Here, we focus on endogenously generated lipids that modulate the sensory TRP activities. Unsaturated fatty acids or their metabolites via lipoxygenase, cyclooxygenase or epoxygenase are able to modulate (activate, inhibit or potentiate) the function of specific TRPs. Isoprene lipids, diacylglycerol, resolvin, and lysophospholipids also show distinct activities on sensory TRP channels. Outcomes caused by the interactions between sensory TRPs and lipid ligands are also discussed. The knowledge we collected here implicates that information on lipidergic ligands may contribute to our understanding of peripheral pain mechanism and provide an opportunity to design novel therapeutic strategies.
Cloning of Xenopus laevis TRPV2 by Gene Prediction
Lee, Jung Youn,Shim, Won Sik,Oh, Uhtaek Korea Genome Organization 2005 Genomics & informatics Vol.3 No.1
TRPV2 is a non-specific cation channel expressed in sensory neurons, and activated by noxious heat. Particularly, TRPV2 has six transmembrane domains and three ankyrin repeats. TRPV2 has been cloned from various species such as human, rat, and mouse. Oocytes of Xenopus laevis - an African clawed frog have been widely used for decades in characterization of various receptors and ion channels. The functional property of rat TRPV2 was also identified by this oocyte expression system. However, no TRPV2 orthologue of Xenopus laevis has been reported so far. Hence, we have focused to clone a TRPV2 orthologue of Xenopus laevis with the aid of bioinformatic tools. Because the genome sequence of Xenopus laevis is not available until now, a genome sequence of Xenopus tropicalis - a close relative species of Xenopus laevis - was used. After a number of bioinformatic searches in silico, a predicted full-length sequence of TRPV2 orthologue of Xenopus tropicalis was found. Based on this predicted sequence, various approaches such as RT-PCR and 5' -RACE technique were applied to clone a full length of Xenopus laevis TRV2. Consequently, a full-length Xenopus laevis TRPV2 was cloned from heart cDNA.
Kim, Sang R,Kim, Seung U,Oh, Uhtaek,Jin, Byung K Williams Wilkins 2006 JOURNAL OF IMMUNOLOGY Vol.177 No.7
<P>The present study examined the expression of transient receptor potential vanilloid subtype 1 (TRPV1) in microglia, and its association with microglial cell death. In vitro cell cultures, RT-PCR, Western blot analysis, and immunocytochemical staining experiments revealed that rat microglia and a human microglia cell line (HMO6) showed TRPV1 expression. Furthermore, exposure of these cells to TRPV1 agonists, capsaicin (CAP) and resiniferatoxin (RTX), triggered cell death. This effect was ameliorated by the TRPV1 antagonists, capsazepine and iodo-resiniferatoxin (I-RTX), suggesting that TRPV1 is directly involved. Further examinations revealed that TRPV1-induced toxicity was accompanied by increases in intracellular Ca(2+), and mitochondrial damage; these effects were inhibited by capsazepine, I-RTX, and the intracellular Ca(2+) chelator BAPTA-AM. Treatment of cells with CAP or RTX led to increased mitochondrial cytochrome c release and enhanced immunoreactivity to cleaved caspase-3. In contrast, the caspase-3 inhibitor z-DEVD-fmk protected microglia from CAP- or RTX-induced toxicity. In vivo, we also found that intranigral injection of CAP or 12-hydroperoxyeicosatetraenoic acid, an endogenous agonist of TRPV1, into the rat brain produced microglial damage via TRPV1 in the substantia nigra, as visualized by immunocytochemistry. To our knowledge, this study is the first to demonstrate that microglia express TRPV1, and that activation of this receptor may contribute to microglial damage via Ca(2+) signaling and mitochondrial disruption.</P>