GSK3 Signaling, second part

GSK3 is a key regulator in several physiological processes, such as cell cycle, oncogenesis and apoptosis in neuronal cells and VSMC (Vascular Smooth Muscle Cells) during hypoxia (Ref.8). Increased cAMP levels promote survival of neuronal cells by inactivating GSK3 via a PKA–dependent mechanism (Ref.4). Many of the pathways that use GSK3 as a regulator have links to human diseases. GSK3 has been implicated in non-insulin-dependent Diabetes Mellitus and generation of NFT (Neurofibrilliary Tangles) associated with Alzheimer’s Disease (Ref.1) as well as several hallmarks of Alzheimer's Disease including neurodegeneration, reactive astrocytosis, microgliosis, and the formation of apoptotic bodies (Ref.8). The tangles are formed from hyperphosphorylated Tau. GSK3-Beta negatively regulates cardiac hypertrophy and cardiac development through its effect on WNT signaling (Ref.4). Recently, a number of potent and selective GSK3 inhibitors have been developed having several therapeutic uses, including the treatment of neurodegenerative disease, bipolar disorder, and inflammatory disease (Ref.8). However, the best-characterized inhibitor of GSK3 is lithium. Although inhibition of GSK3 may be desirable in one context (e.g. in preventing neuronal apoptosis), it could have serious implications for another—for example, it might accelerate hyperplasia by deregulating Beta-Ctnn. Given the involvement of GSK3 in many pathophysiological processes and diseases, GSK3 is a tempting therapeutic target (Ref.1).