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Not only lithium: regulation of glycogen synthase kinase-3 by antipsychotics and serotonergic drugs

Jean-Martin Beaulieu
DOI: http://dx.doi.org/10.1017/S1461145706006857 3-6 First published online: 1 February 2007

Abstract

Multiple recent lines of evidence have underscored the potential role of glycogen synthase kinase-3 (GSK3) as a common molecular signal integrator and therapeutic target for different classes of psychiatric drugs (Figure 1). GSK3α and GSK3β are two closely related serine/threonine kinases originally associated with the regulation of glycogen synthesis in response to insulin (Embi et al., 1980). These constitutively active kinases are regulated negatively through the phosphorylation of single serine residues, Ser21 (GSK3α) and Ser9 (GSK3β), of their regulatory amino-terminal domain (Frame and Cohen, 2001). The protein kinase Akt/PKB has been shown to inhibit both GSK3 isoforms in response to insulin and insulin growth factors (Cross et al., 1995). However, other protein kinases such as PKA and PKC can also regulate GSK3 in different cellular systems (Frame and Cohen, 2001). Apart from its function in glycogenesis, GSK3 plays a role in a host of physiological processes including neurodevelopment, cell proliferation and apoptosis. Moreover, dysregulation of GSK3 function is involved in tumour proliferation as well as in the formation of neurofibrillary tangles in Alzheimer's disease (Woodgett, 2003).