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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.
Painful channels in sensory neurons.
Lee, Yunjong,Lee, Chang-Hun,Oh, Uhtaek Korean Society for Molecular Biology 2005 Molecules and cells Vol.20 No.3
<P>Pain is an unpleasant sensation experienced when tissues are damaged. Thus, pain sensation in some way protects body from imminent threat or injury. Peripheral sensory nerves innervated to peripheral tissues initially respond to multiple forms of noxious or strong stimuli, such as heat, mechanical and chemical stimuli. In response to these stimuli, electrical signals for conducting the nociceptive neural signals through axons are generated. These action potentials are then conveyed to specific areas in the spinal cord and in the brain. Sensory afferent fibers are heterogeneous in many aspects. For example, sensory nerves are classified as Aa, -b, -d and C-fibers according to their diameter and degree of myelination. It is widely accepted that small sensory fibers tend to respond to vigorous or noxious stimuli and related to nociception. Thus these fibers are specifically called nociceptors. Most of nociceptors respond to noxious mechanical stimuli and heat. In addition, these sensory fibers also respond to chemical stimuli [Davis et al. (1993)] such as capsaicin. Thus, nociceptors are considered polymodal. Recent advance in research on ion channels in sensory neurons reveals molecular mechanisms underlying how various types of stimuli can be transduced to neural signals transmitted to the brain for pain perception. In particular, electrophysiological studies on ion channels characterize biophysical properties of ion channels in sensory neurons. Furthermore, molecular biology leads to identification of genetic structures as well as molecular properties of ion channels in sensory neurons. These ion channels are expressed in axon terminals as well as in cell soma. When these channels are activated, inward currents or outward currents are generated, which will lead to depolarization or hyperpolarization of the membrane causing increased or decreased excitability of sensory neurons. In order to depolarize the membrane of nerve terminals, either inward currents should be generated or outward currents should be inhibited. So far, many cationic channels that are responsible for the excitation of sensory neurons are introduced recently. Activation of these channels in sensory neurons is evidently critical to the generation of nociceptive signals. The main channels responsible for inward membrane currents in nociceptors are voltage-activated sodium and calcium channels, while outward current is carried mainly by potassium ions. In addition, activation of non-selective cation channels is also responsible for the excitation of sensory neurons. Thus, excitability of neurons can be controlled by regulating expression or by modulating activity of these channels.</P>