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Zhigang Xiong - One of the best experts on this subject based on the ideXlab platform.

  • zinc Permeable Ion channels effects on intracellular zinc dynamics and potential physiological pathophysiological significance
    Current Medicinal Chemistry, 2015
    Co-Authors: Koichi Inoue, Zaven Obryant, Zhigang Xiong
    Abstract:

    Zinc (Zn 2+ ) is one of the most important trace metals in the body. It is necessary for the normal functIon of a large number of protein s including enzymes and transcriptIon factors. While extracellular fluid may contain up to micromolar Zn 2+ , intracellular Zn 2+ concentratIon is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn 2+ extrusIon by Zn 2+ transporting systems. Interestingly, systematic investigatIon has revealed that activities, previously believed to be dependent on calcium (Ca 2+ ), may be partially mediated by Zn 2+ . This is also supported by new findings that some Ca 2+ -Permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3- hydroxy-5-methyl-4-isoxazolepropIonate receptors (AMPA-Rs) are also Permeable to Zn 2+ . Thus, the importance of Zn 2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn 2+ - Permeable membrane molecules, especially Zn 2+ -Permeable Ion channels, in intracellular Zn 2+ dynamics and Zn 2+ mediated physiology/pathophysiology.

  • Zinc-Permeable Ion channels: effects on intracellular zinc dynamics and potential physiological/pathophysiological significance.
    Current Medicinal Chemistry, 2015
    Co-Authors: Koichi Inoue, Zaven O’bryant, Zhigang Xiong
    Abstract:

    Zinc (Zn 2+ ) is one of the most important trace metals in the body. It is necessary for the normal functIon of a large number of protein s including enzymes and transcriptIon factors. While extracellular fluid may contain up to micromolar Zn 2+ , intracellular Zn 2+ concentratIon is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn 2+ extrusIon by Zn 2+ transporting systems. Interestingly, systematic investigatIon has revealed that activities, previously believed to be dependent on calcium (Ca 2+ ), may be partially mediated by Zn 2+ . This is also supported by new findings that some Ca 2+ -Permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3- hydroxy-5-methyl-4-isoxazolepropIonate receptors (AMPA-Rs) are also Permeable to Zn 2+ . Thus, the importance of Zn 2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn 2+ - Permeable membrane molecules, especially Zn 2+ -Permeable Ion channels, in intracellular Zn 2+ dynamics and Zn 2+ mediated physiology/pathophysiology.

  • calcium Permeable Ion channels involved in glutamate receptor independent ischemic brain injury
    Acta Pharmacologica Sinica, 2011
    Co-Authors: Minghua Li, Koichi Inoue, Hong Fang Si, Zhigang Xiong
    Abstract:

    Brain ischemia is a leading cause of death and long-term disabilities worldwide. Unfortunately, current treatment is limited to thrombolysis, which has limited success and a potential side effect of intracerebral hemorrhage. Searching for new cell injury mechanisms and therapeutic interventIons has become a major challenge in the field. It has been recognized for many years that intracellular Ca2+ overload in neurons is essential for neuronal injury associated with brain ischemia. However, the exact pathway(s) underlying the toxic Ca2+ loading remained elusive. This review discusses the role of two Ca2+-Permeable catIon channels, TRPM7 and acid-sensing channels, in glutamate-independent Ca2+ toxicity associated with brain ischemia.

Donald G. Puro - One of the best experts on this subject based on the ideXlab platform.

  • Calcium Channels of Human Retinal Glial Cells
    Methods in Neurosciences, 2013
    Co-Authors: Donald G. Puro
    Abstract:

    Publisher Summary This chapter describes a method for preparing cultures of glial cells from the adult human retina. It presents applicatIons of various configuratIons of the patch-clamp technique and also studies the retinal glial cells in culture. In preparing cultures from approximately 250 pairs of human donor eyes, three parameters are critical in determining the chances for the successful growth of retinal glial cells: (1) the age of the donor, (2) the time interval between death and enucleatIon, and (3) the length of time from death to retinal dissociatIon. The use of the perforated-patch technique allows the whole-cell calcium currents in human retinal glial cells to be monitored for a relatively long time, that is, greater than one hour. The stability of the amplitudes of the calcium currents is much greater with the perforated-patch configuratIon than with the whole-cell recording technique. A number of different kinds of calcium-Permeable Ion channels are present in human retinal glial cells in culture. Approximately 70% of the retinal glial cells, sampled with the whole-cell recording configuratIon of the patch-clamp technique, have voltage-gated calcium currents. Another type of calcium-Permeable Ion channel, detected in human retinal glial cells, is activated by applying suctIon to the attached patch pipette.

  • a calcium activated calcium Permeable Ion channel in human retinal glial cells modulatIon by basic fibroblast growth factor
    Brain Research, 1991
    Co-Authors: Donald G. Puro
    Abstract:

    Abstract A calcium-Permeable, voltage-insensitive non-specific catIon channel that is activated by cytoplasmic calcium was found in approximately 50% of the cell-attached patches in cultured human retinal glial cells sampled by the patch clamp technique. Spontaneous openings of this channel were infrequent, but increased markedly when glial cells were exposed to basic fibroblast growth factor. Although the role of these catIon channels is uncertain, they provide a mechanism to perpetuate a transient rise in cytosolic calcium induced by the release of calcium from intracellular stores.

Koichi Inoue - One of the best experts on this subject based on the ideXlab platform.

  • zinc Permeable Ion channels effects on intracellular zinc dynamics and potential physiological pathophysiological significance
    Current Medicinal Chemistry, 2015
    Co-Authors: Koichi Inoue, Zaven Obryant, Zhigang Xiong
    Abstract:

    Zinc (Zn 2+ ) is one of the most important trace metals in the body. It is necessary for the normal functIon of a large number of protein s including enzymes and transcriptIon factors. While extracellular fluid may contain up to micromolar Zn 2+ , intracellular Zn 2+ concentratIon is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn 2+ extrusIon by Zn 2+ transporting systems. Interestingly, systematic investigatIon has revealed that activities, previously believed to be dependent on calcium (Ca 2+ ), may be partially mediated by Zn 2+ . This is also supported by new findings that some Ca 2+ -Permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3- hydroxy-5-methyl-4-isoxazolepropIonate receptors (AMPA-Rs) are also Permeable to Zn 2+ . Thus, the importance of Zn 2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn 2+ - Permeable membrane molecules, especially Zn 2+ -Permeable Ion channels, in intracellular Zn 2+ dynamics and Zn 2+ mediated physiology/pathophysiology.

  • Zinc-Permeable Ion channels: effects on intracellular zinc dynamics and potential physiological/pathophysiological significance.
    Current Medicinal Chemistry, 2015
    Co-Authors: Koichi Inoue, Zaven O’bryant, Zhigang Xiong
    Abstract:

    Zinc (Zn 2+ ) is one of the most important trace metals in the body. It is necessary for the normal functIon of a large number of protein s including enzymes and transcriptIon factors. While extracellular fluid may contain up to micromolar Zn 2+ , intracellular Zn 2+ concentratIon is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn 2+ extrusIon by Zn 2+ transporting systems. Interestingly, systematic investigatIon has revealed that activities, previously believed to be dependent on calcium (Ca 2+ ), may be partially mediated by Zn 2+ . This is also supported by new findings that some Ca 2+ -Permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3- hydroxy-5-methyl-4-isoxazolepropIonate receptors (AMPA-Rs) are also Permeable to Zn 2+ . Thus, the importance of Zn 2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn 2+ - Permeable membrane molecules, especially Zn 2+ -Permeable Ion channels, in intracellular Zn 2+ dynamics and Zn 2+ mediated physiology/pathophysiology.

  • calcium Permeable Ion channels involved in glutamate receptor independent ischemic brain injury
    Acta Pharmacologica Sinica, 2011
    Co-Authors: Minghua Li, Koichi Inoue, Hong Fang Si, Zhigang Xiong
    Abstract:

    Brain ischemia is a leading cause of death and long-term disabilities worldwide. Unfortunately, current treatment is limited to thrombolysis, which has limited success and a potential side effect of intracerebral hemorrhage. Searching for new cell injury mechanisms and therapeutic interventIons has become a major challenge in the field. It has been recognized for many years that intracellular Ca2+ overload in neurons is essential for neuronal injury associated with brain ischemia. However, the exact pathway(s) underlying the toxic Ca2+ loading remained elusive. This review discusses the role of two Ca2+-Permeable catIon channels, TRPM7 and acid-sensing channels, in glutamate-independent Ca2+ toxicity associated with brain ischemia.

Shmuel Muallem - One of the best experts on this subject based on the ideXlab platform.

  • Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers.
    Biochimica et Biophysica Acta, 2018
    Co-Authors: Christopher J. Penny, Michela Mazzon, Kristin Vassileva, Xavier Chee, Elizabeth Yates, Bethan S. Kilpatrick, Shmuel Muallem, Yu Yuan, Mark Marsh
    Abstract:

    Abstract Two-pore channels (TPCs) are Ca2+-Permeable Ion channels localised to the endo-lysosomal system where they regulate trafficking of various cargoes including viruses. As a result, TPCs are emerging as important drug targets. However, their pharmacology is ill-defined. There are no approved drugs to target them. And their mechanism of ligand activatIon is largely unknown. Here, we identify a number of FDA-approved drugs as TPC pore blockers. Using a model of the pore of human TPC2 based on recent structures of mammalian TPCs, we virtually screened a database of ~1500 approved drugs. Because TPCs have recently emerged as novel host factors for Ebola virus entry, we reasoned that Ebola virus entry inhibitors may exert their effects through inhibitIon of TPCs. Cross-referencing hits from the TPC virtual screen with two recent high throughput anti-Ebola screens yielded approved drugs targeting dopamine and estrogen receptors as common hits. These compounds inhibited endogenous NAADP-evoked Ca2+ release from sea urchin egg homogenates, NAADP-mediated channel activity of TPC2 re-routed to the plasma membrane, and PI(3,5)P2-mediated channel activity of TPC2 expressed in enlarged lysosomes. Mechanistically, single channel analyses showed that the drugs reduced mean open time consistent with a direct actIon on the pore. FunctIonally, drug potency in blocking TPC2 activity correlated with inhibitIon of Ebola virus-like particle entry. Our results expand TPC pharmacology through the identificatIon of approved drugs as novel blockers, support a role for TPCs in Ebola virus entry, and provide insight into the mechanisms underlying channel regulatIon. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

  • membrane potential regulates nicotinic acid adenine dinucleotide phosphate naadp dependence of the ph and ca2 sensitive organellar two pore channel tpc1
    Journal of Biological Chemistry, 2012
    Co-Authors: Volodymyr Rybalchenko, Sandip Patel, Dev Churamani, Malini Ahuja, Jessica Coblentz, Kirill Kiselyov, Shmuel Muallem
    Abstract:

    Abstract Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent second messenger that mobilizes Ca2+ from the acidic endolysosomes by activatIon of the two-pore channels TPC1 and TPC2. The channel properties of human TPC1 have not been studied before, and its cellular functIon is not known. In the present study, we characterized TPC1 incorporated into lipid bilayers. The native and recombinant TPC1 channels are activated by NAADP. TPC1 activity requires acidic luminal pH and high luminal Ca2+. With Ba2+ as the Permeable Ion, luminal Ca2+ activates TPC1 with an apparent Km of 180 μm. TPC1 operates in two tightly coupled conductance states of 47 ± 8 and 200 ± 9 picosiemens. Importantly, opening of the large conductance markedly increases the small conductance mean open time. Changes in membrane potential from 0 to −60 mV increased linearly both the small and the large conductances and NPo, indicating that TPC1 is regulated by voltage. Intriguingly, the apparent affinity for activatIon of TPC1 by its ligand NAADP is not constant. Rather, hyperpolarizatIon increases the apparent affinity of TPC1 for NAADP by 10 nm/mV. The concerted regulatIon of TPC1 activity by luminal Ca2+ and by membrane potential thus provides a potential mechanism to explain NAADP-induced Ca2+ oscillatIons. These findings reveal unique properties of TPC1 to explain its role in Ca2+ oscillatIons and cell functIon.

  • Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are FunctIonally Independent Organellar Ion Channels
    Journal of Biological Chemistry, 2011
    Co-Authors: Soichiro Yamaguchi, Sandip Patel, Abigail A. Soyombo, George D. Dickinson, Dev Churamani, Eugen Brailoiu, Qin Li, Shmuel Muallem
    Abstract:

    NAADP is a potent second messenger that mobilizes Ca2+ from acidic organelles such as endosomes and lysosomes. The molecular basis for Ca2+ release by NAADP, however, is uncertain. TRP mucolipins (TRPMLs) and two-pore channels (TPCs) are Ca2+-Permeable Ion channels present within the endolysosomal system. Both have been proposed as targets for NAADP. In the present study, we probed possible physical and functIonal associatIon of these Ion channels. Exogenously expressed TRPML1 showed near complete colocalizatIon with TPC2 and partial colocalizatIon with TPC1. TRPML3 overlap with TPC2 was more modest. TRPML1 and to some extent TRPML3 co-immunoprecipitated with TPC2 but less so with TPC1. Current recording, however, showed that TPC1 and TPC2 did not affect the activity of wild-type TRPML1 or constitutively active TRPML1(V432P). N-terminally truncated TPC2 (TPC2delN), which is targeted to the plasma membrane, also failed to affect TRPML1 and TRPML1(V432P) channel functIon or TRPML1(V432P)-mediated Ca2+ influx. Whereas overexpressIon of TPCs enhanced NAADP-mediated Ca2+ signals, overexpressIon of TRPML1 did not, and the dominant negative TRPML1(D471K) was without affect on endogenous NAADP-mediated Ca2+ signals. Furthermore, the single channel properties of NAADP-activated TPC2delN were not affected by TRPML1. Finally, NAADP-evoked Ca2+ oscillatIons in pancreatic acinar cells were identical in wild-type and TRPML1−/− cells. We conclude that although TRPML1 and TPCs are present in the same complex, they functIon as two independent organellar Ion channels and that TPCs, not TRPMLs, are the targets for NAADP.

  • Agonist-mediated Ca2' Release in Permeabilized UMR- 106-O 1 Cells
    1990
    Co-Authors: Hong Zhao, Mahrooz Khademazad, Shmuel Muallem
    Abstract:

    Permeabilized and intact UMR-106-01 cells at- tached to culture plates or coverslips were used to evaluate compartmentalized generatIon and the effec- tive concentratIon of inositol 1,4,5-trisphosphate (In- 1,4,5-P3) during agonist-mediated Ca2+ release. In per- meabilized cells, Ca2+ release had the following char- acteristics. In-1,4,5-P3 released approximately 65% of the Ca2+ incorporated into intracellular stores. Pros- taglandin Fza (PGF&, endothelin, or GTP(rS) alone released a small amount or no Ca’+. However, the agonists together with GTP(rS) were as effective as In-1,4,5-P3 in releasing Ca2+. Both agonist- and In- 1,4,5-Ps-mediated Ca2+ release required the presence of Permeable Ion. Agonists, like In-1,4,5-Pa, stimu- lated 4sCa uptake from low Ca2’ medium devoid of Permeable Ions into Ca2+-loaded intracellular stores. The permeabilized cell system was then used to evalu- ate compartmentalized generatIon and actIon of In- 1,4,5-P3 during agonist stimulatIon. Mass measure- ment shows that in intact resting cells In-1,4,5-PS con- centratIon was 1.4

Kevin J Foskett - One of the best experts on this subject based on the ideXlab platform.

  • calhm1 is an extracellular ca2 and voltage gated atp Permeable Ion channel
    Biophysical Journal, 2013
    Co-Authors: Akiyuki Taruno, Adam P Siebert, Ang Li, Mortimer M Civan, Kevin J Foskett
    Abstract:

    We identified CALHM1 as a pore-forming subunit of a plasma membrane Ion channel with weak Ion selectivity and unique coupled allosteric gating regulatIon by voltage and extracellular Ca2+ (Ca2+o) (PNAS 109: E1963 (2012)). CALHM1 is expressed in mouse cortical neurons where it accounts for low [Ca2+]o-enhanced conductance and actIon potential firing. We recently determined that a CALHM1 channel is a hexamer with an estimated effective pore diameter ∼14A.Extracellular adenosine 5'-triphosphate (ATP) plays critical roles in physiological and signal transductIon processes. We examined whether ATP can permeate CALHM1 channels. Reducing [Ca2+]o to activate CALHM1 induced ATP release from hCALHM1-expressing HeLa and COS-1 cells, and Xenopus oocytes. Neither CALHM1 expressIon nor lowering [Ca2+]o caused cell damage. Involvement of other possible mechanisms was ruled out because ATP release was unaffected by Brefeldin A (vesicular release), DCPIB (volume-sensitive Cl− channels), A438079 (P2X7 receptors), heptanol and carbenoxolone (connexins and pannexins). In contrast, ruthenium red (RuR), which inhibits CALHM1 currents, abolished low [Ca2+]o-evoked ATP release. Thus, CALHM1 expressIon induces a novel ATP permeability. Ca2+o inhibited ATP release with IC50 = 495 μM and Hill coefficient of 1.9, kinetic properties similar to those of its gating regulatIon. Membrane depolarizatIon activates CALHM1 channels in normal [Ca2+]o. hCALHM1-expressing but not mock-transfected cells released ATP in response to high [K+]o-induced depolarizatIon in normal [Ca2+]o, which was inhibited by RuR but not by connexin and pannexin-1 blockers. Thus, regulatIon of ATP release is correlated with the gating properties of CALHM1 channels, indicating that the CALHM1 channel is the conduit for ATP release. These results demonstrate that CALHM1 is a voltage-gated ATP release channel that may contribute to ATP release in physiological and pathological conditIons.

  • calhm1 Ion channel mediates purinergic neurotransmissIon from taste buds to gustatory nerve terminals during sweet and bitter perceptIon
    Biophysical Journal, 2013
    Co-Authors: Akiyuki Taruno, Ang Li, Mortimer M Civan, Philippe Marambaud, Makoto Ohmoto, Ichiro Matsumoto, Michael G Tordoff, Kevin J Foskett
    Abstract:

    Taste buds (TB), composed of three distinct types of cells (type I, II and III), sense taste compounds and transmit signals to afferent gustatory neural pathways. NeurotransmissIon of sweet and bitter tastes requires non-vesicular release from type II cells of adenosine 5'-triphosphate (ATP) which acts as a neurotransmitter to activate afferent neural pathways. However, how ATP is released is uncertain. We recently identified CALHM1 as an ATP-Permeable Ion channel, and CALHM1 was found to be expressed in primate TB. Therefore, we examined the possibility that CALHM1 mediates ATP release from type II cells during sweet and bitter perceptIon. By in situ hybridizatIon, Calhm1 was expressed in mouse TB but not in surrounding epithelium. Loss of Calhm1 signal in TB of Skn-1a-/- mice in which type II cells are developmentally absent demonstrates that Calhm1 expressIon is confined to sweet/bitter-sensing type II cells. To examine CALHM1 functIon, we generated a constitutive Calhm1-/- mouse and verified loss of Calhm1 expressIon in TB. Calhm1-/- mice were viable and fertile, with no overt morphological or marker-gene expressIon abnormalities in their TB. Knockout of Calhm1 significantly reduced voltage-dependent currents in type II cells, which were inhibited by ruthenium red, a CALHM1 channel blocker, but was without effects on the excitability of taste cells to taste stimuli. Strikingly, taste-evoked release ATP release from TB was abolished in Calhm1-/- mice. Finally, Calhm1 deficiency eliminated behavioral responses to sweet and bitter taste stimuli but did not impact salty and sour tastes. Thus, CALHM1 is an essential component of sweet and bitter perceptIon as the neurotransmitter (ATP) release pathway.

  • calcium homeostasis modulator 1 calhm1 is the pore forming subunit of an Ion channel that mediates extracellular ca2 regulatIon of neuronal excitability
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Adam P Siebert, Kingho Cheung, Brian R Johnson, Akiva S Cohen, Valerie Vingtdeux, Philippe Marambaud, Kevin J Foskett
    Abstract:

    Extracellular Ca2+ (Ca2+ o) plays important roles in physiology. Changes of Ca2+o concentratIon ([Ca2+]o) have been observed to modulate neuronal excitability in various physiological and pathophysiological settings, but the mechanisms by which neurons detect [Ca2+]o are not fully understood. Calcium homeostasis modulator 1 (CALHM1) expressIon was shown to induce catIon currents in cells and elevate cytoplasmic Ca2+ concentratIon ([Ca2+]i) in response to removal of Ca2+o and its subsequent addback. However, it is unknown whether CALHM1 is a pore-forming Ion channel or modulates endogenous Ion channels. Here we identify CALHM1 as the pore-forming subunit of a plasma membrane Ca2+-Permeable Ion channel with distinct Ion permeability properties and unique coupled allosteric gating regulatIon by voltage and [Ca2+]o. Furthermore, we show that CALHM1 is expressed in mouse cortical neurons that respond to reducing [Ca2+]o with enhanced conductance and actIon potential firing and strongly elevated [Ca2+]i upon Ca2+o removal and its addback. In contrast, these responses are strongly muted in neurons from mice with CALHM1 genetically deleted. These results demonstrate that CALHM1 is an evolutIonarily conserved Ion channel family that detects membrane voltage and extracellular Ca2+ levels and plays a role in cortical neuronal excitability and Ca2+ homeostasis, particularly in response to lowering [Ca2+]o and its restoratIon to normal levels.