| N-glycosylation determines ionic permeability and desensitization of the TRPV1 capsaicin receptor. | |
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MedLine Citation:
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PMID: 22570472 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The balance of glycosylation and deglycosylation of ion channels can markedly influence their function and regulation. However, the functional importance of glycosylation of the TRPV1 receptor, a key sensor of pain-sensing nerves, is not well understood, and whether TRPV1 is glycosylated in neurons is unclear. We report that TRPV1 is N-glycosylated and that N-glycosylation is a major determinant of capsaicin-evoked desensitization and ionic permeability. Both N-glycosylated and unglycosylated TRPV1 was detected in extracts of peripheral sensory nerves by Western blotting. TRPV1 expressed in HEK-293 cells exhibited various degrees of glycosylation. A mutant of asparagine 604 (N604T) was not glycosylated but did not alter plasma membrane expression of TRPV1. Capsaicin-evoked increases in intracellular calcium ([Ca(2+)](i)) were sustained in wild-type TRPV1 HEK-293 cells but were rapidly desensitized in N604T TRPV1 cells. There was marked cell-to-cell variability in capsaicin responses and desensitization between individual cells expressing wild-type TRPV1 but highly uniform responses in cells expressing N604T TRPV1, consistent with variable levels of glycosylation of the wild-type channel. These differences were also apparent when wild-type or N604T TRPV1-GFP fusion proteins were expressed in neurons from trpv1(-/-) mice. Capsaicin evoked a marked, concentration-dependent increase in uptake of the large cationic dye YO-PRO-1 in cells expressing wild-type TRPV1, indicative of loss of ion selectivity, that was completely absent in cells expressing N604T TRPV1. Thus, TRPV1 is variably N-glycosylated and glycosylation is a key determinant of capsaicin regulation of TRPV1 desensitization and permeability. Our findings suggest that physiological or pathological alterations in TRPV1 glycosylation would affect TRPV1 function and pain transmission. |
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Authors:
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Nicholas A Veldhuis; Michael J Lew; Fe C Abogadie; Daniel P Poole; Ernest A Jennings; Jason J Ivanusic; Helge Eilers; Nigel W Bunnett; Peter McIntyre |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-05-08 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-06-25 Completed Date: 2012-09-20 Revised Date: 2013-04-16 |
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: 21765-72 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, University of Melbourne, Parkville, Victoria, 3010, Australia. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biotinylation Cell Membrane / metabolism Coloring Agents / pharmacology Dose-Response Relationship, Drug Genetic Vectors Glycosylation HEK293 Cells Humans Ions Male Mice Mice, Transgenic Neurons / metabolism Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / chemistry Permeability Protein Binding Protein Structure, Tertiary Rats TRPV Cation Channels / chemistry*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK39957/DK/NIDDK NIH HHS; DK43207/DK/NIDDK NIH HHS; DK57840/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Coloring Agents; 0/Ions; 0/TRPV Cation Channels; 0/TRPV1 receptor; EC 3.5.1.52/Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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