Constitutive sodium permeability in a C. elegans two-pore domain potassium channel.

Autor:	Andrini O; University Claude Bernard Lyon 1, MeLiS, CNRS UMR 5284, INSERM U1314, Lyon 69008, France., Ben Soussia I; University Claude Bernard Lyon 1, MeLiS, CNRS UMR 5284, INSERM U1314, Lyon 69008, France., Tardy P; University Claude Bernard Lyon 1, MeLiS, CNRS UMR 5284, INSERM U1314, Lyon 69008, France., Walker DS; Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom., Peña-Varas C; Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepcion 4070386, Chile., Ramírez D; Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepcion 4070386, Chile., Gendrel M; Institut de Biologie de l'École Normale Supérieure, École Normale Supérieure, CNRS UMR 8197, INSERM U1024, Université Paris Sciences et Lettres, Paris 75005, France., Mercier M; University Claude Bernard Lyon 1, MeLiS, CNRS UMR 5284, INSERM U1314, Lyon 69008, France., El Mouridi S; University Claude Bernard Lyon 1, MeLiS, CNRS UMR 5284, INSERM U1314, Lyon 69008, France., Leclercq-Blondel A; University Claude Bernard Lyon 1, MeLiS, CNRS UMR 5284, INSERM U1314, Lyon 69008, France., González W; Center for Bioinformatics, Simulation and Modelling, University of Talca, Talca 3460000, Chile., Schafer WR; Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.; Department of Biology, Katholieke Universiteit Leuven, Leuven 3000, Belgium., Jospin M; University Claude Bernard Lyon 1, MeLiS, CNRS UMR 5284, INSERM U1314, Lyon 69008, France., Boulin T; University Claude Bernard Lyon 1, MeLiS, CNRS UMR 5284, INSERM U1314, Lyon 69008, France.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 22; Vol. 121 (43), pp. e2400650121. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1073/pnas.2400650121
Abstrakt:	Two-pore domain potassium (K2P) channels play a central role in modulating cellular excitability and neuronal function. The unique structure of the selectivity filter in K2P and other potassium channels determines their ability to allow the selective passage of potassium ions across cell membranes. The nematode C. elegans has one of the largest K2P families, with 47 subunit-coding genes. This remarkable expansion has been accompanied by the evolution of atypical selectivity filter sequences that diverge from the canonical TxGYG motif. Whether and how this sequence variation may impact the function of K2P channels has not been investigated so far. Here, we show that the UNC-58 K2P channel is constitutively permeable to sodium ions and that a cysteine residue in its selectivity filter is responsible for this atypical behavior. Indeed, by performing in vivo electrophysiological recordings and Ca 2+ imaging experiments, we demonstrate that UNC-58 has a depolarizing effect in muscles and sensory neurons. Consistently, unc-58 gain-of-function mutants are hypercontracted, unlike the relaxed phenotype observed in hyperactive mutants of many neuromuscular K2P channels. Finally, by combining molecular dynamics simulations with functional studies in Xenopus laevis oocytes, we show that the atypical cysteine residue plays a key role in the unconventional sodium permeability of UNC-58. As predicting the consequences of selectivity filter sequence variations in silico remains a major challenge, our study illustrates how functional experiments are essential to determine the contribution of such unusual potassium channels to the electrical profile of excitable cells. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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