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The Amyloid Precursor Protein C99 Fragment Modulates Voltage-Gated Potassium Channels.
Manville RW
,
Abbott GW
.
Abstract
BACKGROUND/AIMS: The Amyloid Precursor Protein (APP) is involved in the regulation of multiple cellular functions via protein-protein interactions and has been most studied with respect to Alzheimer's disease (AD). Abnormal processing of the single transmembrane-spanning C99 fragment of APP contributes to the formation of amyloid plaques, which are causally related to AD. Pathological C99 accumulation is thought to associate with early cognitive defects in AD. Here, unexpectedly, sequence analysis revealed that C99 exhibits 24% sequence identity with the KCNE1 voltage-gated potassium (Kv) channel β subunit, comparable to the identity between KCNE1 and KCNE2-5 (21-30%). This suggested the possibility of C99 regulating Kv channels.
METHODS: We quantified the effects of C99 on Kv channel function, using electrophysiological analysis of subunits expressed in Xenopus laevis oocytes, biochemical and immunofluorescence techniques.
RESULTS: C99 isoform-selectively inhibited (by 30-80%) activity of a range of Kv channels. Among the KCNQ (Kv7) family, C99 isoform-selectively inhibited, shifted the voltage dependence and/or slowed activation of KCNQ2, KCNQ3, KCNQ2/3 and KCNQ5, with no effects on KCNQ1, KCNQ1-KCNE1 or KCNQ4. C99/APP co-localized with KCNQ2 and KCNQ3 in adult rat sciatic nerve nodes of Ranvier. Both C99 and full-length APP co-immunoprecipitated with KCNQ2 in vitro, yet unlike C99, APP only weakly affected KCNQ2/3 activity. Finally, C99 altered the effects on KCNQ2/3 function of inhibitors tetraethylammounium and XE991, but not openers retigabine and ICA27243.
CONCLUSION: Our findings raise the possibility of C99 accumulation early in AD altering cellular excitability by modulating Kv channel activity.
Abbott,
The KCNE2 K⁺ channel regulatory subunit: Ubiquitous influence, complex pathobiology.
2015,
Pubmed
Abbott,
KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation.
2016,
Pubmed
Abbott,
KCNE4 and KCNE5: K(+) channel regulation and cardiac arrhythmogenesis.
2017,
Pubmed
Abbott,
MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis.
2001,
Pubmed
,
Xenbase
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999,
Pubmed
,
Xenbase
Abbott,
KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability.
2014,
Pubmed
,
Xenbase
Armstrong,
Time course of TEA(+)-induced anomalous rectification in squid giant axons.
2001,
Pubmed
Armstrong,
The inner quaternary ammonium ion receptor in potassium channels of the node of Ranvier.
1972,
Pubmed
Bonham,
Neurotransmitter Pathway Genes in Cognitive Decline During Aging: Evidence for GNG4 and KCNQ2 Genes.
2019,
Pubmed
Bourgeois,
Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3×TgAD and 2×TgAD mice.
2019,
Pubmed
Delpón,
Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.
2009,
Pubmed
Devaux,
KCNQ2 is a nodal K+ channel.
2004,
Pubmed
Drici,
Involvement of IsK-associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome.
1998,
Pubmed
Etxeberria,
Three mechanisms underlie KCNQ2/3 heteromeric potassium M-channel potentiation.
2005,
Pubmed
,
Xenbase
Greene,
XE991 and Linopirdine Are State-Dependent Inhibitors for Kv7/KCNQ Channels that Favor Activated Single Subunits.
2017,
Pubmed
Grosdidier,
SwissDock, a protein-small molecule docking web service based on EADock DSS.
2011,
Pubmed
Grosdidier,
Fast docking using the CHARMM force field with EADock DSS.
2015,
Pubmed
Johansson,
Defining and searching for structural motifs using DeepView/Swiss-PdbViewer.
2013,
Pubmed
Kim,
Atomic basis for therapeutic activation of neuronal potassium channels.
2016,
Pubmed
,
Xenbase
Lange,
Refinement of the binding site and mode of action of the anticonvulsant Retigabine on KCNQ K+ channels.
2009,
Pubmed
,
Xenbase
Lauritzen,
Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology.
2017,
Pubmed
Lauritzen,
The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus.
2013,
Pubmed
Lee,
Kcne2 deletion promotes atherosclerosis and diet-dependent sudden death.
2016,
Pubmed
Lee,
Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus.
2017,
Pubmed
Li,
Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway.
2018,
Pubmed
,
Xenbase
Manville,
Direct neurotransmitter activation of voltage-gated potassium channels.
2018,
Pubmed
,
Xenbase
Neverisky,
KCNQ-SMIT complex formation facilitates ion channel-solute transporter cross talk.
2017,
Pubmed
,
Xenbase
Ohno,
KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation.
2011,
Pubmed
Padilla,
The KCNQ2/3 selective channel opener ICA-27243 binds to a novel voltage-sensor domain site.
2010,
Pubmed
Park,
N-Glycosylation-dependent block is a novel mechanism for drug-induced cardiac arrhythmia.
2004,
Pubmed
Puig,
Expression and function of APP and its metabolites outside the central nervous system.
2014,
Pubmed
Roepke,
Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f).
2008,
Pubmed
Roepke,
Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis.
2009,
Pubmed
Roepke,
Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia.
2010,
Pubmed
Schenzer,
Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine.
2006,
Pubmed
,
Xenbase
Splawski,
Mutations in the hminK gene cause long QT syndrome and suppress IKs function.
1997,
Pubmed
,
Xenbase
Sun,
Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.
2017,
Pubmed
,
Xenbase
Vetter,
Inner ear defects induced by null mutation of the isk gene.
1997,
Pubmed
Weckhuysen,
KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy.
2012,
Pubmed
Xu,
Amyloid precursor protein at node of Ranvier modulates nodal formation.
2015,
Pubmed
Young-Pearse,
A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference.
2008,
Pubmed
