Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: the role of GSK-3beta in the maintenance of steady-state levels of insulin receptor signaling molecules and Na(v)1.7 sodium channel in adrenal chromaffin cells.
Glycogen synthase kinase-3 (GSK-3) is constitutively active in nonstimulated cells, where the majority of its substrates undergo inactivation/proteolysis by phosphorylation. Extracellular stimuli (e.g., insulin) catalyze inhibitory Ser(9)-phosphorylation of GSK-3beta, turning on signaling and causing other biological consequences otherwise constitutively suppressed by GSK-3beta. Regulated and dysregulated activities of GSK-3beta are pivotal to health, disease, and therapeutics (e.g., insulin resistance, neurodegeneration, tumorigenesis, inflammation); however, the underlying mechanisms of multifunctional GSK-3beta remain elusive. In cultured bovine adrenal chromaffin cells, 1) constitutive and negatively-regulated activities of GSK-3beta up- and down-regulated insulin receptor, insulin receptor substrate-1 (IRS-1), IRS-2, and Akt levels via controlling proteasomal degradation and protein synthesis; 2) nicotinic receptor/protein kinase C-alpha (PKC-alpha)/extracellular signal-regulated kinase (ERK) pathway up-regulated IRS-1 and IRS-2 levels, enhancing insulin-induced the phosphoinositide 3-kinase (PI3K)/Akt/GSK-3beta pathway; 3) inhibition of calcineurin by cyclosporin A or FK506 down-regulated IRS-2 level, attenuating insulin-like growth factor-I (IGF-I)-induced ERK and GSK-3beta pathways; and 4) insulin, IGF-I or therapeutics (e.g., lithium) up-regulated the voltage-dependent Na(v)1.7 sodium channel.
Nemoto
Takayuki
T
Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Japan. tnemoto@fc.miyazaki-u.ac.jp
Yanagita
Toshihiko
T
Kanai
Tasuku
T
Wada
Akihiko
A
D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D019439:Chromaffin Cells / Q000378:metabolism*; D015536:Down-Regulation; D016503:Drug Delivery Systems; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D015222:Sodium Channels / Q000378:metabolism*; D015854:Up-Regulation
D015222:Sodium Channels; D011972:Receptor, Insulin; D038362:Glycogen Synthase Kinase 3