Pathogenic residue insertion in neuronal nicotinic receptor alters intra- and inter-subunit interactions that tune channel gating.

ABSTRACT: We describe molecular-level functional changes in the α4β2 nicotinic acetylcholine receptor by a leucine residue insertion in the M2 transmembrane domain of the α4 subunit associated with sleep-related hyperkinetic epilepsy. Measurements of agonist-elicited single-channel currents reveal the primary effect is to stabilize the open channel state, while the secondary effect is to promote reopening of the channel. These dual effects prolong the durations of bursts of channel openings equally for the two major stoichiometric forms of the receptor, (α4)₂(β2)₃ and (α4)₃(β2)₂, indicating the functional impact is independent of mutant copy number per receptor. Altering the location of the residue insertion within M2 shows that functionally pivotal struct

SUBMITTER: Msekela DJ 

PROVIDER: S-EPMC11067541 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature