The Glycogen Synthase Kinase-3 in the Regulation of Ion Channels and Cellular Carriers

Abstract

Glycogen synthase kinase-3 (GSK-3) is a highly evolutionarily conserved and ubiquitously expressed serine/threonine kinase, an enzyme protein profoundly specific for glycogen synthase (GS). GSK-3 is involved in various cellular functions and physiological processes, including cell proliferation, differentiation, motility, and survival as well as glycogen metabolism, protein synthesis, and apoptosis. There are two isoforms of human GSK-3 (named GSK-3α and GSK-3β) encoded by two distinct genes. Recently, GSK-3β has been reported to function as a powerful regulator of various transport processes across the cell membrane. This kinase, GSK-3β, either directly or indirectly, may stimulate or inhibit many different types of transporter proteins, including ion channel and cellular carriers. More specifically, GSK-3β-sensitive cellular transport regulation involves various calcium, chloride, sodium, and potassium ion channels, as well as a number of Na+-coupled cellular carriers including excitatory amino acid transporters EAAT2, 3 and 4, high-affinity Na+ coupled glucose carriers SGLT1, creatine transporter 1 CreaT1, and the type II sodium/phosphate cotransporter NaPi-IIa. The GSK-3β-dependent cellular transport regulations are a part of the kinase functions in numerous physiological and pathophysiological processes. Clearly, additional studies are required to examine the role of GSK-3β in many other types of cellular transporters as well as further elucidating the underlying mechanisms of GSK-3β-mediated cellular transport regulation.

Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

“…GSK-3 is well known to regulate many different ion channels, and specifically, GSK-3β regulates various calcium, chloride, sodium, and potassium ion channels in the nervous system. 64 A study in adrenal chromaffin cells showed that, in addition to regulating GSK-3, lithium may also directly inhibit sodium-channel function. 65 Lithium-induced proarrhythmic effects have been described to occur through dosage-dependent block of peak sodium current.…”

Neuroprotective Effects of Krypton Inhalation on Photothrombotic Ischemic Stroke

“…Analysis of the key signaling pathways associated with ischemic tolerance showed that the amount of the phosphorylated form of AKT kinase (protein kinase B) in brain tissue increased significantly ( p = 0.0012) when the animals were exposed to krypton for 2 h. However, the total amount of the AKT protein did not change. Similarly, a trend toward increased levels of phosphorylated GSK3b kinase was observed in the brain, which are downstream in the signaling cascade and associated with preconditioning [ 19 , 20 ] The signal for pGSK3b was normalized to the total GSK3b protein, whose levels were also unchanged after exposure to krypton.…”

The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication

“…The activated AKT promotes glycolysis indirectly through its downstream GSK-3β, which can phosphorylate a panel of proteins/transcription factors related to metabolism. [97][98][99][100] More importantly, PI3K/AKT activates mammalian target of rapamycin (mTOR). mTOR constructs two different complex isoforms, namely mTOR complex 1 and 2 (mTORC1/2).…”