| Identification of direct and indirect effectors of the transient receptor potential melastatin 2 (TRPM2) cation channel. | |
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MedLine Citation:
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PMID: 20650899 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+)-permeable cation channel involved in physiological and pathophysiological processes linked to oxidative stress. TRPM2 channels are co-activated by intracellular Ca(2+) and ADP-ribose (ADPR) but also modulated in intact cells by several additional factors. Superfusion of TRPM2-expressing cells with H(2)O(2) or intracellular dialysis of cyclic ADPR (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP) activates, whereas dialysis of AMP inhibits, TRPM2 whole-cell currents. Additionally, H(2)O(2), cADPR, and NAADP enhance ADPR sensitivity of TRPM2 currents in intact cells. Because in whole-cell recordings the entire cellular machinery for nucleotide and Ca(2+) homeostasis is intact, modulators might affect TRPM2 activity either directly, by binding to TRPM2, or indirectly, by altering the local concentrations of the primary ligands ADPR and Ca(2+). To identify direct modulators of TRPM2, we have studied the effects of H(2)O(2), AMP, cADPR, NAADP, and nicotinic acid adenine dinucleotide in inside-out patches from Xenopus oocytes expressing human TRPM2, by directly exposing the cytosolic faces of the patches to these compounds. H(2)O(2) (1 mM) and enzymatically purified cADPR (10 μM) failed to activate, whereas AMP (200 μM) failed to inhibit TRPM2 currents. NAADP was a partial agonist (maximal efficacy, ∼50%), and nicotinic acid adenine dinucleotide was a full agonist, but both had very low affinities (K(0.5) = 104 and 35 μM). H(2)O(2), cADPR, and NAADP did not enhance activation by ADPR. Considering intracellular concentrations of these compounds, none of them are likely to directly affect the TRPM2 channel protein in a physiological context. |
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Authors:
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Balázs Tóth; László Csanády |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-20 Completed Date: 2010-10-21 Revised Date: 2012-04-27 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 30091-102 Citation Subset: IM |
Affiliation:
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Department of Medical Biochemistry, Semmelweis University, Budapest H-1094, Hungary. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Diphosphate Ribose
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pharmacology Animals Calcium / metabolism Cyclic ADP-Ribose / pharmacology Humans Hydrogen Peroxide / pharmacology NAD / analogs & derivatives*, pharmacology NADP / analogs & derivatives, pharmacology Oxidants / pharmacology Oxidative Stress / drug effects*, physiology TRPM Cation Channels / agonists*, genetics, metabolism* Xenopus laevis |
| Chemical | |
Reg. No./Substance:
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0/Oxidants; 0/TRPM Cation Channels; 0/TRPM2 protein, human; 119340-53-3/Cyclic ADP-Ribose; 20762-30-5/Adenosine Diphosphate Ribose; 53-59-8/NADP; 53-84-9/NAD; 5502-96-5/NAADP; 6450-77-7/nicotinic acid adenine dinucleotide; 7440-70-2/Calcium; 7722-84-1/Hydrogen Peroxide |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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