Disease Associated Mutations in KIR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking

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.

Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ(1–42)-Infused Rat Model of Alzheimer’s Disease

“…They are involved in a number of essential physiological processes, such as the regulation of hormone secretion, generation of electrical impulses, and control of vascular smooth muscle tone. It is known that a variety of severe human disorders are directly related to a dysfunction of Kir channel proteins [17]. Moreover, intracellular Na + and K + levels were found to be increased in brain regions of AD patients, pointing out a cellular ion imbalance in AD pathophysiology [18].…”

Determinants of trafficking, conduction, and disease within a K+ channel revealed through multiparametric deep mutational scanning

“…Many mutations linked to neonatal diabetes reduced Kir6.2 surface expression to varying degrees 17 . Beyond known trafficking signals (e.g., ER and Golgi-export signal sequences [18][19][20][21][22][23] ), mutations along the entire Kir primary sequence can disrupt surface expression 16 . Several additional factors control surface expression, such as protein stability, interactions with trafficking partners, and complexes that stabilize channels in the membrane 20,24,25 .…”

Phylogenomics of Tick Inward Rectifier Potassium Channels and Their Potential as Targets to Innovate Control Technologies

“…In mammals, Kir channels are expressed by diverse tissues comprising the nervous, muscle, cardiovascular, and urinary systems ( Walsh, 2020 ). Consequently, abnormal function of Kir channels has been implicated in human diseases affecting these organ systems ( Zangerl-Plessl et al., 2019 ). Mutations that cause trafficking defects associated with Kir channel dysfunction have been identified and primarily occur in two “hotspots”: in and around the TM1 domain and in a segment of the C-terminal cytoplasmic region ( Zangerl-Plessl et al., 2019 ).…”