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Article: Mechanism of Ca 2+ Disruption in Alzheimer's Disease by Presenilin Regulation of InsP 3 Receptor Channel Gating

TitleMechanism of Ca 2+ Disruption in Alzheimer's Disease by Presenilin Regulation of InsP 3 Receptor Channel Gating
Authors
KeywordsHUMDISEASE
MOLNEURO
Issue Date2008
PublisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/neuron
Citation
Neuron, 2008, v. 58 n. 6, p. 871-883 How to Cite?
AbstractMutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca 2+) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L) and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP 3R) Ca 2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP 3. These interactions result in exaggerated cellular Ca 2+ signaling in response to agonist stimulation as well as enhanced low-level Ca 2+ signaling in unstimulated cells. Parallel studies in InsP 3R-expressing and -deficient cells revealed that enhanced Ca 2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP 3R stimulates amyloid beta processing, an important feature of AD pathology. These observations provide molecular insights into the "Ca 2+ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention. © 2008 Elsevier Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/132534
ISSN
2015 Impact Factor: 13.974
2015 SCImago Journal Rankings: 11.464
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCheung, KHen_HK
dc.contributor.authorShineman, Den_HK
dc.contributor.authorMüller, Men_HK
dc.contributor.authorCárdenas, Cen_HK
dc.contributor.authorMei, Len_HK
dc.contributor.authorYang, Jen_HK
dc.contributor.authorTomita, Ten_HK
dc.contributor.authorIwatsubo, Ten_HK
dc.contributor.authorLee, VMYen_HK
dc.contributor.authorFoskett, JKen_HK
dc.date.accessioned2011-03-28T09:26:02Z-
dc.date.available2011-03-28T09:26:02Z-
dc.date.issued2008en_HK
dc.identifier.citationNeuron, 2008, v. 58 n. 6, p. 871-883en_HK
dc.identifier.issn0896-6273en_HK
dc.identifier.urihttp://hdl.handle.net/10722/132534-
dc.description.abstractMutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca 2+) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L) and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP 3R) Ca 2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP 3. These interactions result in exaggerated cellular Ca 2+ signaling in response to agonist stimulation as well as enhanced low-level Ca 2+ signaling in unstimulated cells. Parallel studies in InsP 3R-expressing and -deficient cells revealed that enhanced Ca 2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP 3R stimulates amyloid beta processing, an important feature of AD pathology. These observations provide molecular insights into the "Ca 2+ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention. © 2008 Elsevier Inc. All rights reserved.en_HK
dc.languageengen_US
dc.publisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/neuronen_HK
dc.relation.ispartofNeuronen_HK
dc.subjectHUMDISEASEen_HK
dc.subjectMOLNEUROen_HK
dc.titleMechanism of Ca 2+ Disruption in Alzheimer's Disease by Presenilin Regulation of InsP 3 Receptor Channel Gatingen_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.doi10.1016/j.neuron.2008.04.015en_HK
dc.identifier.pmid18579078-
dc.identifier.pmcidPMC2495086-
dc.identifier.scopuseid_2-s2.0-45249117227en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-45249117227&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume58en_HK
dc.identifier.issue6en_HK
dc.identifier.spage871en_HK
dc.identifier.epage883en_HK
dc.identifier.eissn1097-4199-
dc.identifier.isiWOS:000257171700008-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f10001117920-
dc.identifier.scopusauthoridCheung, KH=14007487800en_HK
dc.identifier.scopusauthoridShineman, D=7801388113en_HK
dc.identifier.scopusauthoridMüller, M=7404689330en_HK
dc.identifier.scopusauthoridCárdenas, C=7003841618en_HK
dc.identifier.scopusauthoridMei, L=7103211483en_HK
dc.identifier.scopusauthoridYang, J=9239264300en_HK
dc.identifier.scopusauthoridTomita, T=7403060061en_HK
dc.identifier.scopusauthoridIwatsubo, T=7102672132en_HK
dc.identifier.scopusauthoridLee, VMY=35350846200en_HK
dc.identifier.scopusauthoridFoskett, JK=7005723620en_HK
dc.identifier.citeulike5846583-

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