DOWN-REGULATION OF Kir2.6 CHANNEL BY C-TERMINI MUTATION D252N AND ITS ASSOCIATION WITH THE SUSCEPTIBILITY TO THYROTOXIC PERIODIC PARALYSIS
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2017
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Paninka, Rolf Matias [UNIFESP]
Carlos-Lima, Estevao [UNIFESP]
Lindsey, Susan C. [UNIFESP]
Kunii, Ilda S. [UNIFESP]
Dias-Da-Silva, Magnus R. [UNIFESP]
Arcisio-Miranda, Manoel [UNIFESP]
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Inward 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 (similar to 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 similar to 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. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
whereas the mutation R386C shows no significant changes from WT. The mutant D252N Kir2.6 channel also showed a substantial reduction of similar to 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. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
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Neuroscience. Oxford, v. 346, p. 197-202, 2017.