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Article: Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons

TitleGain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2010
PublisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://stke.sciencemag.org/
Citation
Science Signaling, 2010, v. 3 n. 114, p. ra22 How to Cite?
AbstractFamilial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1 and PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca2+) homeostasis bymechanisms proximal to and independent of amyloid production, although the molecular details are controversial. We found that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (IP3R) Ca2+ release channel by a gain-of-function effect that mirrored the genetics of FAD and was independent of secretase activity. In contrast, wild-type PS or PS mutants that cause frontotemporal dementia had no such effect. FAD-causing PS mutants altered the modes in which the IP3R channel gated. Recordings of endogenous IP3R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed they were more likely than IP 3R in cells with wild-type PS to dwell in a high open-probability burst mode, resulting in enhanced Ca2+ signaling. These results indicate that exaggerated Ca2+ signaling through IP3R-PS interaction is a disease-specific and robust proximal mechanism in FAD. Copyright 2008 by the American Association for the Advancement of Science; all rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/132533
ISSN
2015 Impact Factor: 7.359
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCheung, KHen_HK
dc.contributor.authorMei, Len_HK
dc.contributor.authorMak, DODen_HK
dc.contributor.authorHayashi, Ien_HK
dc.contributor.authorIwatsubo, Ten_HK
dc.contributor.authorKang, DEen_HK
dc.contributor.authorFoskett, JKen_HK
dc.date.accessioned2011-03-28T09:26:02Z-
dc.date.available2011-03-28T09:26:02Z-
dc.date.issued2010en_HK
dc.identifier.citationScience Signaling, 2010, v. 3 n. 114, p. ra22en_HK
dc.identifier.issn1945-0877en_HK
dc.identifier.urihttp://hdl.handle.net/10722/132533-
dc.description.abstractFamilial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1 and PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca2+) homeostasis bymechanisms proximal to and independent of amyloid production, although the molecular details are controversial. We found that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (IP3R) Ca2+ release channel by a gain-of-function effect that mirrored the genetics of FAD and was independent of secretase activity. In contrast, wild-type PS or PS mutants that cause frontotemporal dementia had no such effect. FAD-causing PS mutants altered the modes in which the IP3R channel gated. Recordings of endogenous IP3R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed they were more likely than IP 3R in cells with wild-type PS to dwell in a high open-probability burst mode, resulting in enhanced Ca2+ signaling. These results indicate that exaggerated Ca2+ signaling through IP3R-PS interaction is a disease-specific and robust proximal mechanism in FAD. Copyright 2008 by the American Association for the Advancement of Science; all rights reserved.en_HK
dc.languageengen_US
dc.publisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://stke.sciencemag.org/en_HK
dc.relation.ispartofScience Signalingen_HK
dc.subjectChemicals And Cas Registry Numbersen_US
dc.titleGain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neuronsen_HK
dc.typeArticleen_HK
dc.identifier.emailCheung, KH: kingho.cheung@hku.hken_HK
dc.identifier.authorityCheung, KH=rp01463en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1126/scisignal.2000818en_HK
dc.identifier.pmid20332427-
dc.identifier.pmcidPMC2898196-
dc.identifier.scopuseid_2-s2.0-77953644150en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77953644150&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume3en_HK
dc.identifier.issue114en_HK
dc.identifier.spagera22en_HK
dc.identifier.epagera22en_HK
dc.identifier.eissn1937-9145-
dc.identifier.isiWOS:000276228400005-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridCheung, KH=14007487800en_HK
dc.identifier.scopusauthoridMei, L=7103211483en_HK
dc.identifier.scopusauthoridMak, DOD=35587181700en_HK
dc.identifier.scopusauthoridHayashi, I=7202283628en_HK
dc.identifier.scopusauthoridIwatsubo, T=7102672132en_HK
dc.identifier.scopusauthoridKang, DE=7402889417en_HK
dc.identifier.scopusauthoridFoskett, JK=7005723620en_HK
dc.identifier.citeulike10654670-

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