• Rolf Matias Paninka, Estevão Carlos-Lima, Susan C Lindsey, Ilda S Kunii, Magnus R Dias-da-Silva, and Manoel Arcisio-Miranda.
• Laboratório de Neurobiologia Estrutural e Funcional, Departamento de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil; Laboratório de Endocrinologia Molecular e Translacional, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
• Neuroscience. 2017 Mar 27; 346: 197-202.

AbstractInward rectifying potassium - Kir - channels drive the resting potential to potassium reversal potential and, when disrupted, might be related to muscular diseases. Recently, Thyrotoxic Periodic Paralysis (TPP) has emerged as a channelopathy related to mutations in KCNJ18 gene, which encodes Kir2.6 channel. TPP is a neuromuscular disorder characterized by a triad of muscle weakness, hypokalemia, and thyrotoxicosis, the latter being essential for the crisis. Direct sequencing revealed two heterozygous mutations - D252N and R386C - in two TPP patients. KCNJ18 cDNAs were cloned into mammalian expression plasmids and transiently expressed in HEK 293T cells to investigate the functional effects of Kir2.6 mutations. Patch-clamp and confocal laser scanning microscopy experiments were carried out, comparing the WT channel to its mutants. D252N mutation down-regulates the Kir2.6 activity, decreasing the K+ current density (∼34%) when compared to the WT channel; whereas the mutation R386C shows no significant changes from WT. The mutant D252N Kir2.6 channel also showed a substantial reduction of ∼51% in membrane abundance relative to WT channel. Our study describes the functional consequences of a single amino acid change in Kir2.6 channel. Further analysis regarding hormonal conditions and Kir channel expression are required to provide new clues about the TPP pathophysiology.Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

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