The Amyloid Precursor Protein C99 Fragment Modulates Voltage-Gated Potassium Channels.
Amino Acid Sequence
Amyloid beta-Protein Precursor
/ genetics
Animals
Anthracenes
/ pharmacology
Gene Expression
Humans
KCNQ Potassium Channels
/ genetics
KCNQ2 Potassium Channel
/ genetics
KCNQ3 Potassium Channel
/ genetics
Membrane Potentials
/ drug effects
Oocytes
/ cytology
Patch-Clamp Techniques
Peptide Fragments
/ genetics
Ranvier's Nodes
/ drug effects
Rats
Recombinant Proteins
/ genetics
Sciatic Nerve
/ drug effects
Sequence Alignment
Sequence Homology, Amino Acid
Tetraethylammonium
/ pharmacology
Xenopus laevis
Alzheimer’s disease; Potassium channel; KCNE; KCNQ2; KCNQ3
Journal
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
ISSN: 1421-9778
Titre abrégé: Cell Physiol Biochem
Pays: Germany
ID NLM: 9113221
Informations de publication
Date de publication:
28 Jul 2021
28 Jul 2021
Historique:
accepted:
13
07
2021
entrez:
28
7
2021
pubmed:
29
7
2021
medline:
2
9
2021
Statut:
ppublish
Résumé
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. We quantified the effects of C99 on Kv channel function, using electrophysiological analysis of subunits expressed in Xenopus laevis oocytes, biochemical and immunofluorescence techniques. 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. Our findings raise the possibility of C99 accumulation early in AD altering cellular excitability by modulating Kv channel activity.
Sections du résumé
BACKGROUND/AIMS
OBJECTIVE
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
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
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
CONCLUSIONS
Our findings raise the possibility of C99 accumulation early in AD altering cellular excitability by modulating Kv channel activity.
Identifiants
pubmed: 34318654
doi: 10.33594/000000397
pmc: PMC8610427
mid: NIHMS1756635
doi:
Substances chimiques
10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone
0
APP protein, human
0
Amyloid beta-Protein Precursor
0
Anthracenes
0
KCNQ Potassium Channels
0
KCNQ2 Potassium Channel
0
KCNQ3 Potassium Channel
0
Kcnq2 protein, rat
0
Kcnq3 protein, rat
0
Kcnq5 protein, rat
0
Peptide Fragments
0
Recombinant Proteins
0
Tetraethylammonium
66-40-0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
157-170Subventions
Organisme : NINDS NIH HHS
ID : R01 NS107671
Pays : United States
Organisme : NINDS - National Institute of Neurological Disorders and Stroke
ID : NS107671-02S1
Pays : United States
Informations de copyright
© Copyright by the Author(s). Published by Cell Physiol Biochem Press.
Déclaration de conflit d'intérêts
The authors declare that no conflict of interests exists.
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