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Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1
β-Secretase 1 (β-site amyloid precursor protein [APP]-cleaving enzyme 1, BACE1) plays a crucial role in the amyloidogenesis of Alzheimer’s disease (AD). BACE1 was also discovered to act like an auxiliary subunit to modulate neuronal KCNQ2/3 channels independently of its proteolytic function. BACE1 i...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Rockefeller University Press
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876601/ https://www.ncbi.nlm.nih.gov/pubmed/35201266 http://dx.doi.org/10.1085/jgp.202112888 |
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author | Dai, Gucan |
author_facet | Dai, Gucan |
author_sort | Dai, Gucan |
collection | PubMed |
description | β-Secretase 1 (β-site amyloid precursor protein [APP]-cleaving enzyme 1, BACE1) plays a crucial role in the amyloidogenesis of Alzheimer’s disease (AD). BACE1 was also discovered to act like an auxiliary subunit to modulate neuronal KCNQ2/3 channels independently of its proteolytic function. BACE1 is palmitoylated at its carboxyl-terminal region, which brings BACE1 to ordered, cholesterol-rich membrane microdomains (lipid rafts). However, the physiological consequences of this specific localization of BACE1 remain elusive. Using spectral Förster resonance energy transfer (FRET), BACE1 and KCNQ2/3 channels were confirmed to form a signaling complex, a phenomenon that was relatively independent of the palmitoylation of BACE1. Nevertheless, palmitoylation of BACE1 was required for recruitment of KCNQ2/3 channels to lipid-raft domains. Two fluorescent probes, designated L10 and S15, were used to label lipid-raft and non-raft domains of the plasma membrane, respectively. Coexpressing BACE1 substantially elevated FRET between L10 and KCNQ2/3, whereas the BACE1-4C/A quadruple mutation failed to produce this effect. In contrast, BACE1 had no significant effect on FRET between S15 probes and KCNQ2/3 channels. A reduction of BACE1-dependent FRET between raft-targeting L10 probes and KCNQ2/3 channels by applying the cholesterol-extracting reagent methyl-β-cyclodextrin (MβCD), raft-disrupting general anesthetics, or pharmacological inhibitors of palmitoylation, all supported the hypothesis of the palmitoylation-dependent and raft-specific localization of KCNQ2/3 channels. Furthermore, mutating the four carboxyl-terminal cysteines (4C/A) of BACE1 abolished the BACE1-dependent increase of FRET between KCNQ2/3 and the lipid raft–specific protein caveolin 1. Taking these data collectively, we propose that the AD-related protein BACE1 underlies the localization of a neuronal potassium channel. |
format | Online Article Text |
id | pubmed-8876601 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-88766012022-10-04 Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1 Dai, Gucan J Gen Physiol Article β-Secretase 1 (β-site amyloid precursor protein [APP]-cleaving enzyme 1, BACE1) plays a crucial role in the amyloidogenesis of Alzheimer’s disease (AD). BACE1 was also discovered to act like an auxiliary subunit to modulate neuronal KCNQ2/3 channels independently of its proteolytic function. BACE1 is palmitoylated at its carboxyl-terminal region, which brings BACE1 to ordered, cholesterol-rich membrane microdomains (lipid rafts). However, the physiological consequences of this specific localization of BACE1 remain elusive. Using spectral Förster resonance energy transfer (FRET), BACE1 and KCNQ2/3 channels were confirmed to form a signaling complex, a phenomenon that was relatively independent of the palmitoylation of BACE1. Nevertheless, palmitoylation of BACE1 was required for recruitment of KCNQ2/3 channels to lipid-raft domains. Two fluorescent probes, designated L10 and S15, were used to label lipid-raft and non-raft domains of the plasma membrane, respectively. Coexpressing BACE1 substantially elevated FRET between L10 and KCNQ2/3, whereas the BACE1-4C/A quadruple mutation failed to produce this effect. In contrast, BACE1 had no significant effect on FRET between S15 probes and KCNQ2/3 channels. A reduction of BACE1-dependent FRET between raft-targeting L10 probes and KCNQ2/3 channels by applying the cholesterol-extracting reagent methyl-β-cyclodextrin (MβCD), raft-disrupting general anesthetics, or pharmacological inhibitors of palmitoylation, all supported the hypothesis of the palmitoylation-dependent and raft-specific localization of KCNQ2/3 channels. Furthermore, mutating the four carboxyl-terminal cysteines (4C/A) of BACE1 abolished the BACE1-dependent increase of FRET between KCNQ2/3 and the lipid raft–specific protein caveolin 1. Taking these data collectively, we propose that the AD-related protein BACE1 underlies the localization of a neuronal potassium channel. Rockefeller University Press 2022-02-23 /pmc/articles/PMC8876601/ /pubmed/35201266 http://dx.doi.org/10.1085/jgp.202112888 Text en © 2022 Dai https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Dai, Gucan Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1 |
title | Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1 |
title_full | Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1 |
title_fullStr | Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1 |
title_full_unstemmed | Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1 |
title_short | Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1 |
title_sort | neuronal kcnq2/3 channels are recruited to lipid raft microdomains by palmitoylation of bace1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876601/ https://www.ncbi.nlm.nih.gov/pubmed/35201266 http://dx.doi.org/10.1085/jgp.202112888 |
work_keys_str_mv | AT daigucan neuronalkcnq23channelsarerecruitedtolipidraftmicrodomainsbypalmitoylationofbace1 |