| Molecular mechanisms of EAST/SeSAME syndrome mutations in Kir4.1 (KCNJ10). | |
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MedLine Citation:
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PMID: 20807765 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Inwardly rectifying potassium channel Kir4.1 is critical for glial function, control of neuronal excitability, and systemic K(+) homeostasis. Novel mutations in Kir4.1 have been associated with EAST/SeSAME syndrome, characterized by mental retardation, ataxia, seizures, hearing loss, and renal salt waste. Patients are homozygous for R65P, G77R, C140R or T164I; or compound heterozygous for A167V/R297C or R65P/R199Stop, a deletion of the C-terminal half of the protein. We investigated the functional significance of these mutations by radiotracer efflux and inside-out membrane patch clamping in COSm6 cells expressing homomeric Kir4.1 or heteromeric Kir4.1/Kir5.1 channels. All of the mutations compromised channel function, but the underlying mechanisms were different. R65P, T164I, and R297C caused an alkaline shift in pH sensitivity, indicating that these positions are crucial for pH sensing and pore gating. In R297C, this was due to disruption of intersubunit salt bridge Glu(288)-Arg(297). C140R breaks the Cys(108)-Cys(140) disulfide bond essential for protein folding and function. A167V did not affect channel properties but may contribute to decreased surface expression in A167V/R297C. In G77R, introduction of a positive charge within the bilayer may affect channel structure or gating. R199Stop led to a dramatic decrease in surface expression, but channel activity was restored by co-expression with intact subunits, suggesting remarkable tolerance for truncation of the cytoplasmic domain. These results provide an explanation for the molecular defects that underlie the EAST/SeSAME syndrome. |
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Authors:
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Monica Sala-Rabanal; Lilia Y Kucheryavykh; Serguei N Skatchkov; Misty J Eaton; Colin G Nichols |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-31 |
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 Nov |
Date Detail:
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Created Date: 2010-11-08 Completed Date: 2011-02-09 Revised Date: 2011-11-14 |
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: 36040-8 Citation Subset: IM |
Affiliation:
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Department of Cell Biology and Physiology, Washington University, St Louis, Missouri 63110, USA. msala@wustl.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Abnormalities, Multiple
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genetics*,
pathology Amino Acid Sequence Animals Ataxia / pathology Cell Line Hearing Loss, Sensorineural / pathology Humans Hydrogen-Ion Concentration Ion Channel Gating / genetics*, physiology Membrane Potentials Mental Retardation / pathology Models, Molecular Molecular Sequence Data Mutation* Patch-Clamp Techniques Potassium / metabolism Potassium Channels, Inwardly Rectifying / chemistry, genetics*, physiology Protein Multimerization Protein Structure, Tertiary Rats Seizures / pathology Sequence Homology, Amino Acid Syndrome Transfection |
| Grant Support | |
ID/Acronym/Agency:
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G12-RR03035/RR/NCRR NIH HHS; HL54171/HL/NHLBI NIH HHS; R01 NS065201-02/NS/NINDS NIH HHS; S11-NS48201/NS/NINDS NIH HHS; U54-NS039408/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Kir5.1channel; 0/Potassium Channels, Inwardly Rectifying; 0/potassium inwardly-rectifying channel, subfamily J, member 10; 7440-09-7/Potassium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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