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.
Highlights
1.1 KCNJ FamilyPotassium homeostasis is needed for cell health and cellular potassium (K+) balance is tightly regulated
The Kir channels are encoded by 16 KCNJ genes and their function impacts a wide range of cellular processes
We provide a synopsis of Kir2.x family members, focusing on Kir2.1 trafficking pathways and roles in embryonic development
Summary
Potassium homeostasis is needed for cell health and cellular potassium (K+) balance is tightly regulated. K+ is essential for normal functioning of nerve and muscle cells due to its contribution to membrane potential (Bia and DeFronzo, 1981; Youn and McDonough, 2009). A family of inwardly-rectifying potassium (Kir) channels plays a central role in this regulation. The Kir channels are encoded by 16 KCNJ genes and their function impacts a wide range of cellular processes. For. FIGURE 1 | site [orange]), Cav binding site (CBS, bright green and one dark green where it overlaps with a cholesterol binding site), PIP2 binding residues (red and one orange where it overlaps with a cholesterol binding site), Yxxφ motif (pink), AP-1 binding site (blue), GRIF-1 interaction region (tan), and ER export signal (purple). Purple arrows indicate well-studied trafficking routes for Kir2.1 whereas the red arrow denotes a putative endosome-Golgi recycling pathway.
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