Resolution of the interaction site within 4R0N-tau mediating augmentation of L-type calcium current

Abstract

L-type calcium channels (LTCCs) are voltage gated calcium channels comprised of three subunits: an α1 pore forming subunit and β and α₂δ auxillary subunits. LTCC’s have a range of cellular functions, including activating potassium channels which are responsible for afterhyperpolarisations (AHPs): potentials which contribute to regulation of neuronal firing. Preliminary evidence suggests that 4R0N tau, a microtubule associated protein known to be overexpressed with age and in Alzheimer’s disease (AD), can increase the amount of LTCC at the cell membrane of hippocampal neurons. This occurs if Ca_v1.2 is the pore forming subunit for the LTCC and β₃ is the β auxillary subunit. An increase in LTCCs at the cell membrane augments macroscopic calcium current and, subsequently, decreases the rate of neuronal firing by increasing the size of currents underlying the AHP. Here, current-voltage relationships for Ca_v1.2 mediated current have been generated in the absence and presence of 4R0N tau, using whole cell electrophysiology in tsA-201 cells. This demonstrated that 4R0N tau can significantly augment Ca_v1.2 mediated current. It has been hypothesised that a direct interaction between 4R0N tau and Ca_vβ is responsible for augmentation of Ca_v1.2 mediated current. Here, mutants of 4R0N tau have been generated to identify residues involved in this interaction. It has been shown that mutation of residues in the second proline rich domain of tau (P155/P158) abolish the ability of 4R0N tau to augment Ca_v1.2 mediated current. An excess of 4R0N tau and upregulation LTCCs has been reported in individuals with AD, as well as in aged animals experiencing cognitive decline. Therefore, resolution of the site on 4R0N-tau mediating augmentation of calcium current may open new avenues for therapeutics in the treatment of cognitive decline with age and in AD.

Date of Award	24 Jan 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Neil V Marrion (Supervisor) & Jonathan G Hanley (Supervisor)