Inwardly Rectifying Potassium Channel Kir2.1 and its “Kir-ious” Regulation by Protein Trafficking and Roles in Development and Disease

Abstract

Potassium (K+) homeostasis is tightly regulated for optimal cell and organismal health. Failure to control potassium balance results in disease, including cardiac arrythmias and developmental disorders. A family of inwardly rectifying potassium (Kir) channels helps cells maintain K+ levels. Encoded by KCNJ genes, Kir channels are comprised of a tetramer of Kir subunits, each of which contains two-transmembrane domains. The assembled Kir channel generates an ion selectivity filter for K+ at the monomer interface, which allows for K+ transit. Kir channels are found in many cell types and influence K+ homeostasis across the organism, impacting muscle, nerve and immune function. Kir2.1 is one of the best studied family members with well-defined roles in regulating heart rhythm, muscle contraction and bone development. Due to their expansive roles, it is not surprising that Kir mutations lead to disease, including cardiomyopathies, and neurological and metabolic disorders. Kir malfunction is linked to developmental defects, including underdeveloped skeletal systems and cerebellar abnormalities. Mutations in Kir2.1 cause the periodic paralysis, cardiac arrythmia, and developmental deficits associated with Andersen-Tawil Syndrome. Here we review the roles of Kir family member Kir2.1 in maintaining K+ balance with a specific focus on our understanding of Kir2.1 channel trafficking and emerging roles in development and disease. We provide a synopsis of the vital work focused on understanding the trafficking of Kir2.1 and its role in development.

Deep Insertion, Deletion, and Missense Mutation Libraries for Exploring Protein Variation in Evolution, Disease, and Biology

“…Our initial target, Kir2.1, is a potassium channel with a variety of physiological roles, primarily setting the resting membrane potential of a cell (Hager et al 2021). Many mutations, including deletions, impact Kir2.1 surface expression and cause severe cardiac and developmental disorders (Hager et al 2021; Donghui Ma et al 2007). To understand how indels affect Kir2.1 physiology, we performed an assay to specifically identify mutational impacts on surface trafficking.…”

On-demand cell-autonomous gene therapy for brain circuit disorders

“…S10 and S11 ). When the KCNJ2 transgene was used, however, neurons exhibited a hyperpolarized resting membrane potential, as expected from the intrinsic properties of this channel ( 32 ), but inconsistent changes in firing ( figs. S10 and S11 and supplementary text).…”

“…S6 ). We compared the promoters of several IEGs ( cfos , arc , and egr1 ) as well as synthetic activity−dependent promoters [enhanced synaptic activity-responsive element (ESARE) and NPAS4 robust activity marker (NRAM)], which have different properties ( 21 , 29 – 31 ) ( table S2 ), in combination with three transgenes: the control reporter dsGFP; EKC as above; or another potassium channel gene, KCNJ2 , which encodes the muscle inward-rectifier Kir2.1 ( 32 , 33 ). Although some promoter-transgene combinations were effective in reducing spiking and/or bursting, none was as consistent across the different electrophysiological measures as cfos -EKC ( fig.…”

Mutational Insight into Allosteric Regulation of Kir Channel Activity

“…Inward-rectifier K + (Kir) channels are integral membrane proteins with important physiological roles in mammalian excitable cells, notably the heart, brain, kidney, and pancreas. − Although these channels can pass potassium ions (K + ) in both the directions of the membrane, they have a higher tendency to conduct potassium into the cell. − Thus, these channels drive and establish a charge gradient necessary for crucial processes such as restoring resting potentials in the cardiac tissue, insulin secretion, and muscle contraction. , There are a number of human diseases that are associated with dysfunction and mutation of Kir channels . These include, but are not limited to, Bartter syndrome which affects kidney, CNS, and vascular function in Kir1.1, Andersen–Tawil syndrome that causes cardiac arrhythmias and skeletal abnormalities, neurocognitive disorders including Parkinson’s and short/long QT syndrome in Kir2.X, epilepsy, addiction, alcohol abuse, and familial hyperaldosteronism in Kir3.X, transient neonatal diabetes or hyperinsulinism in Kir6.X, and snowflake vitreoretinal degeneration in Kir7.X . Thus, a better understanding of the channel pathophysiology and disease state mutations could be monitored by the dynamics of key residues in the allosteric network involved in Kir channel gating.…”

“… 5 , 9 There are a number of human diseases that are associated with dysfunction and mutation of Kir channels. 10 These include, but are not limited to, Bartter syndrome which affects kidney, CNS, and vascular function in Kir1.1, 10 Andersen–Tawil syndrome that causes cardiac arrhythmias and skeletal abnormalities, neurocognitive disorders including Parkinson’s and short/long QT syndrome in Kir2.X, 11 epilepsy, addiction, alcohol abuse, and familial hyperaldosteronism in Kir3.X, 12 transient neonatal diabetes or hyperinsulinism in Kir6.X, 13 and snowflake vitreoretinal degeneration in Kir7.X. 14 Thus, a better understanding of the channel pathophysiology and disease state mutations could be monitored by the dynamics of key residues in the allosteric network involved in Kir channel gating.…”