Accessibility navigation

Protofibrillar amyloid beta modulation of recombinant hCaV2.2 (N-type) voltage-gated channels

Kaisis, E., Thei, L. J., Stephens, G. J. ORCID: and Dallas, M. L. ORCID: (2022) Protofibrillar amyloid beta modulation of recombinant hCaV2.2 (N-type) voltage-gated channels. Pharmaceuticals, 15 (12). 1459. ISSN 1424-8247

Text (Open access) - Published Version
· Available under License Creative Commons Attribution.
· Please see our End User Agreement before downloading.

[img] Text - Accepted Version
· Restricted to Repository staff only


It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing.

To link to this item DOI: 10.3390/ph15121459


Cav2.2 channels are key regulators of presynaptic Ca2+ influx and their dysfunction and/or aber-rant regulation has been implicated in many disease states; however, the nature of their involve-ment in Alzheimer’s disease (AD) is less clear. In this short communication, we show that recombinant hCav2.2/beta1b/a2d channels are modulated by human synthetic AD-related protofibrillar amyloid beta Abeta1-42 peptide. Structural studies revealed a time-dependent increase in protofibril length, with the majority of protofibrils less than 100nm at 24hr; while at 48 hr, the majority were longer than 100nm. Cav2.2 modulation by Abeta1-42 was different between a ‘low’ (100nM) and ‘high’ (1µM) concentration in terms of distinct effects on individual biophysical parameters. 100nM Abeta1-42 caused a significant change in the slope factor (k) consistent with improved voltage sensitivity of the channel; by contrast, 1µM Abeta1-42 caused an inhibitory decrease in current density (pA/pF) and maximum conductance (Gmax). These data highlight a differential modulation of Cav2.2 channels by Abeta1-42 peptide. Discrete changes in presynaptic Ca2+ flux have been reported to occur at an early stage of AD; therefore, this study has implications for targeting Cav2.2 in the AD pathology and reveals a potential mechanistic link between amyloid accumulation and Cav2.2 channel modulation.

Item Type:Article
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
ID Code:109167


Downloads per month over past year

University Staff: Request a correction | Centaur Editors: Update this record

Page navigation