This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the manuscript and its Supporting information files.įunding: Support was provided to MMW from the Barrow Neurological Foundation and an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (NIH 2P20GM103395). Received: NovemAccepted: FebruPublished: March 3, 2021Ĭopyright: © 2021 Weltzin et al. PLoS ONE 16(3):Įditor: Israel Silman, Weizmann Institute of Science, ISRAEL Further mechanistic context is provided by intracellular-domain structures recently published for other members of the Cys-loop receptor superfamily (α3β4-nAChR and 5-HT 3AR).Ĭitation: Weltzin MM, George AA, Lukas RJ, Whiteaker P (2021) Sleep-related hypermotor epilepsy associated mutations uncover important kinetic roles of α4β2- nicotinic acetylcholine receptor intracellular structures. The use of naturally-occurring and physiologically-impactful mutations has allowed us to define valuable new insights regarding the functional roles of nAChR intracellular domains. By contrast, the β2(V337G) mutation principally stabilizes receptor open states. The α4(R336H) mutation primarily destabilizes desensitized states between openings. However, for both mutant subunits, increased function-per-receptor was predominantly caused by altered single channel kinetics. α4(R336H) subunit incorporation minimally affected single-channel amplitudes, whereas β2(V337G) subunit incorporation reduced them significantly in both isoforms. Functional properties of the resulting mutant α4β2-nAChR isoforms were compared to their wildtype counterparts. Pure populations of HS- or LS-isoform α4β2-nAChR were expressed by injecting either 1:10 or 30:1 α4:β2 cRNA ratios, respectively, into Xenopus laevis oocytes. Here, we use single-channel patch-clamp electrophysiology to show that these mutations influence single-channel amplitudes and open- and closed-state kinetics. We recently demonstrated that two additional, SHE-associated, missense mutations in the major cytoplasmic loops of these subunits cause increased macroscopic function-per receptor. Multiple non-synonymous mutations in the second and third transmembrane domains of α4 and β2 subunits are associated with SHE. (α4β2) 2β2-nAChR have high agonist sensitivity (HS-isoform), whereas (α4β2) 2α4-nAChR agonist responses exhibit a small high-sensitivity, and a predominant low-sensitivity, phase of function (LS-isoform). The most prevalent central nervous system nAChR subtype contains α4 and β2 subunits, in two ratios. Sleep-related hypermotor epilepsy (SHE) is a group of seizure disorders prominently associated with mutations in nicotinic acetylcholine receptors (nAChR).
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