Molecular mechanisms underlying LINGO2 effects on BK channels

Zainab, Baig (2026) Molecular mechanisms underlying LINGO2 effects on BK channels. Doctoral thesis, Dundalk Institute of Technology.

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Abstract

Large conductance Ca2+- and voltage-activated potassium (BK) channels are widely expressed ion channels that regulate diverse physiological processes, including smooth muscle contraction, neurotransmission and epithelial fluid secretion. Their activity is modulated by auxiliary subunits, including the LINGO family, which can induce channel inactivation and alter voltage-dependent activation. LINGO1 and LINGO2 share substantial sequence similarity but differ in their effects on BK channel expression and regulation. The aim of this thesis was to define the molecular mechanisms underlying LINGO2-mediated modulation of BK channels, with particular emphasis on the structural interactions responsible for inactivation and shifts in voltage-dependent activation. Inside-out patch-clamp electrophysiology, site-directed mutagenesis and molecular modelling were used to investigate interactions between LINGO2 and BK channels. The findings demonstrate that LINGO2-mediated inactivation results from hydrophobic docking of its distal cytosolic tail within the BK channel pore. In particular, interactions with pore-accessible residues in the BK S6 helix, including F315, are critical for stabilising pore block. A conserved hydrophobic cluster within the distal LINGO2 tail also contributes to inactivation, with combined disruption of multiple residues producing a marked reduction in inactivation while preserving channel activation. LINGO2-mediated shifts in voltage-dependent activation were further shown to involve a distributed intracellular mechanism rather than a single electrostatic salt bridge between LINGO2 and the BK RCK1 domain. Finally, residue-swapping experiments identified the juxta membrane residue corresponding to D578 in LINGO2 as an important determinant of isoform-specific shifts in BK channel activation. Collectively, these findings establish distinct but interacting molecular mechanisms through which LINGO2 regulates BK channel function and provide new insight into the structural basis of LINGO-dependent modulation of ion channel activity.

Item Type:	Thesis (Doctoral)
Subjects:	Science > Biology
Research Centres:	UNSPECIFIED
Depositing User:	Mark Hollywood
Date Deposited:	13 Aug 2026 23:30
Last Modified:	13 Aug 2026 23:30
License:	Creative Commons: Attribution-Noncommercial-Share Alike 4.0
URI:	https://eprints.dkit.ie/id/eprint/1071

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