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

Kaisis, E., Thei, L. J., Stephens, G. J. ORCID: https://orcid.org/0000-0002-8966-4238 and Dallas, M. L. ORCID: https://orcid.org/0000-0002-5190-0522 (2022) Protofibrillar amyloid beta modulation of recombinant hCaV2.2 (N-type) voltage-gated channels. Pharmaceuticals, 15 (12). 1459. ISSN 1424-8247 doi: 10.3390/ph15121459

Abstract/Summary

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
URI	https://reading-clone.eprints-hosting.org/id/eprint/109167
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	MDPI
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