Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated Channels
Cav2.2 channels are key regulators of presynaptic Ca<sup>2+</sup> influx and their dysfunction and/or aberrant regulation has been implicated in many disease states; however, the nature of their involvement in Alzheimer’s disease (AD) is less clear. In this short communication, we show t...
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MDPI AG
2022-11-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/12/1459 |
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| author | Eleni Kaisis Laura J. Thei Gary J. Stephens Mark L. Dallas |
| author_facet | Eleni Kaisis Laura J. Thei Gary J. Stephens Mark L. Dallas |
| author_sort | Eleni Kaisis |
| collection | DOAJ |
| description | Cav2.2 channels are key regulators of presynaptic Ca<sup>2+</sup> influx and their dysfunction and/or aberrant regulation has been implicated in many disease states; however, the nature of their involvement in Alzheimer’s disease (AD) is less clear. In this short communication, we show that recombinant hCav2.2/b<sub>1b</sub>/a<sub>2</sub>d<sub>1</sub> channels are modulated by human synthetic AD-related protofibrillar amyloid beta Ab<sub>1-42</sub> peptides. Structural studies revealed a time-dependent increase in protofibril length, with the majority of protofibrils less than 100 nm at 24 h, while at 48 h, the majority were longer than 100 nm. Cav2.2 modulation by Ab<sub>1-42</sub> was different between a ‘low’ (100 nM) and ‘high’ (1 µM) concentration in terms of distinct effects on individual biophysical parameters. A concentration of 100 nM Ab<sub>1-42</sub> caused no significant changes in the measured biophysical properties of Cav2.2 currents. In contrast, 1 µM Ab<sub>1-42</sub> caused an inhibitory decrease in the current density (pA/pF) and maximum conductance (Gmax), and a depolarizing shift in the slope factor (k). These data highlight a differential modulation of Cav2.2 channels by the Ab<sub>1-42</sub> peptide. Discrete changes in the presynaptic Ca<sup>2+</sup> flux have been reported to occur at an early stage of AD; therefore, this study reveals a potential mechanistic link between amyloid accumulation and Ca<sub>v</sub>2.2 channel modulation. |
| first_indexed | 2024-03-09T15:59:29Z |
| format | Article |
| id | doaj.art-8fc899a6a6a04957b360d09f7ba072aa |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T15:59:29Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-8fc899a6a6a04957b360d09f7ba072aa2023-11-24T17:15:32ZengMDPI AGPharmaceuticals1424-82472022-11-011512145910.3390/ph15121459Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated ChannelsEleni Kaisis0Laura J. Thei1Gary J. Stephens2Mark L. Dallas3School of Pharmacy, University of Reading, Reading RG6 6UB, UKSchool of Pharmacy, University of Reading, Reading RG6 6UB, UKSchool of Pharmacy, University of Reading, Reading RG6 6UB, UKSchool of Pharmacy, University of Reading, Reading RG6 6UB, UKCav2.2 channels are key regulators of presynaptic Ca<sup>2+</sup> influx and their dysfunction and/or aberrant regulation has been implicated in many disease states; however, the nature of their involvement in Alzheimer’s disease (AD) is less clear. In this short communication, we show that recombinant hCav2.2/b<sub>1b</sub>/a<sub>2</sub>d<sub>1</sub> channels are modulated by human synthetic AD-related protofibrillar amyloid beta Ab<sub>1-42</sub> peptides. Structural studies revealed a time-dependent increase in protofibril length, with the majority of protofibrils less than 100 nm at 24 h, while at 48 h, the majority were longer than 100 nm. Cav2.2 modulation by Ab<sub>1-42</sub> was different between a ‘low’ (100 nM) and ‘high’ (1 µM) concentration in terms of distinct effects on individual biophysical parameters. A concentration of 100 nM Ab<sub>1-42</sub> caused no significant changes in the measured biophysical properties of Cav2.2 currents. In contrast, 1 µM Ab<sub>1-42</sub> caused an inhibitory decrease in the current density (pA/pF) and maximum conductance (Gmax), and a depolarizing shift in the slope factor (k). These data highlight a differential modulation of Cav2.2 channels by the Ab<sub>1-42</sub> peptide. Discrete changes in the presynaptic Ca<sup>2+</sup> flux have been reported to occur at an early stage of AD; therefore, this study reveals a potential mechanistic link between amyloid accumulation and Ca<sub>v</sub>2.2 channel modulation.https://www.mdpi.com/1424-8247/15/12/1459ion channelamyloid betavoltage-gated calcium channelneurodegenerationAlzheimer’s disease |
| spellingShingle | Eleni Kaisis Laura J. Thei Gary J. Stephens Mark L. Dallas Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated Channels Pharmaceuticals ion channel amyloid beta voltage-gated calcium channel neurodegeneration Alzheimer’s disease |
| title | Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated Channels |
| title_full | Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated Channels |
| title_fullStr | Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated Channels |
| title_full_unstemmed | Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated Channels |
| title_short | Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated Channels |
| title_sort | protofibrillar amyloid beta modulation of recombinant hcav2 2 n type voltage gated channels |
| topic | ion channel amyloid beta voltage-gated calcium channel neurodegeneration Alzheimer’s disease |
| url | https://www.mdpi.com/1424-8247/15/12/1459 |
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