Abstract
The ubiquitously expressed family of inward rectifier potassium (KIR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the central and peripheral neural system, heart, kidney, pancreas, and skeletal muscle. A number of mutations associate with altered ion channel expression at the plasma membrane, which might result from defective channel trafficking. Trafficking involves cellular processes that transport ion channels to and from their place of function. By alignment of all KIR channels, and depicting the trafficking associated mutations, three mutational hotspots were identified. One localized in the transmembrane-domain 1 and immediately adjacent sequences, one was found in the G-loop and Golgi-export domain, and the third one was detected at the immunoglobulin-like domain. Surprisingly, only few mutations were observed in experimentally determined Endoplasmic Reticulum (ER)exit-, export-, or ER-retention motifs. Structural mapping of the trafficking defect causing mutations provided a 3D framework, which indicates that trafficking deficient mutations form clusters. These “mutation clusters” affect trafficking by different mechanisms, including protein stability.
Highlights
Seventy years ago, Katz detected the inward rectification phenomenon for the first time [1].Its unexpected property of conducting larger inward than outward potassium currents at similar deviations from the potassium equilibrium potential was unprecedented at that time
Two Bartter syndrome associated KIR 1.1 (Y314C; L320P) and two Andersen–Tawil signal patch was found to be formed by a C-terminal stretch of hydrophobic residues and basic syndrome associated KIR 2.1 confirmed trafficking mutations have been described in residues from the N-terminus [16,17]
This, as well as previous work [55], suggests that this structural motif might be a crucial hotspot implicated in trafficking of Mutations in KIR potassium ion channels associate with a variety of human diseases in which electrophysiological and potassium homeostasis aberrations are explaining etiology
Summary
Katz detected the inward rectification phenomenon for the first time [1]. KIR2 and KIR3, are often expressed in excitable cells such as neuronal or muscle cells Their rectifying properties enable cells to conserve K+ during action potential formation and facilitate K+ entry upon cell hyperpolarization. KIR 3, are often expressedapplication in excitable of cells as neuronal or muscle cells Application of μM barium, at that concentration rather specific atrioventricular node (AVN) [6]; KIR3 is mainly expressed in the atrium with much lower levels infor the KIR 2 channel lengthenede.g., the action potential papillary muscle preparations by ventricle. Various diseases associate with mutations in KCNJ rectifier channel trafficking with protein domains important for trafficking by means of channel genes. Rectifier channel trafficking with protein domains important for trafficking by means of channel alignment, and to put mutational changes in a structural framework.
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