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

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). GSK3a and GSK3b 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 (GSK3a) and Ser9 (GSK3b), 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). The first suggestion of an involvement of GSK3 in the biological action of psychotropic drugs came from the identification of the mood stabilizer lithium as a direct GSK3 inhibitor (Klein and Melton, 1996). Interestingly, lithium can also inhibit GSK3 activity in cells through an indirect mechanism (Figure 1) involving Akt activation (Beaulieu et al., 2004 ; Chalecka-Franaszek and Chuang, 1999 ; Zhang et al., 2003). Acute and chronic administration of lithium has been shown to inhibit brain GSK3 activity in mice as revealed by enhanced regulatory amino-terminal domain phosphorylation (Beaulieu et al., 2004 ; De Sarno et al., 2002). Moreover, GSK3 inhibitors or reduction of GSK3b expression by genetic manipulation both reproduces some of the behavioural action of lithium in rodents indicating that inhibition of GSK3 may contribute to lithium’s psychopharmacological actions (Beaulieu et al., 2004 ; O’Brien et al., 2004). Further investigation of the involvement of GSK3 in mood disorders has revealed that GSK3b can be regulated by antidepressants acting on serotonergic (5-HT) neurotransmission (Li et al., 2004). Administration of either specific serotonin reuptake inhibitors (SSRIs) or monoamine oxidase (MAO) inhibitors to mice results in a substantial increased phosphorylation (deactivation) of brain GSK3 (Figure 1). Moreover, GSK3 inhibitors have been shown to have some antidepressant-like effects in rodents (Gould et al., 2004) while electroconvulsive shock therapy, a common approach for the management of drug-resistant depression, may also affect GSK3 regulation (Roh et al., 2003). Interestingly, antidepressants are sometimes used in conjunction with lithium to increase their efficacy (De Montigny et al., 1981). Two 5-HT receptors appear to play important and antagonistic roles in regulating GSK3b, stimulation of 5-HT1A receptors leading to kinase inhibition while stimulation of 5-HT2A receptors has the opposite effect (Li et al., 2004). Finally, recent evidence revealed a link between dysregulation of the Akt/GSK3 signalling pathways, schizophrenia and dopaminergic neurotransmission (Figure 1). Significant association of Akt1 haplotypes with schizophrenia has been reported following transmission disequilibrium tests while reduced Akt protein levels were shown in the brains of schizophrenic patients (Emamian et al., 2004). Typical antipsychotics such as haloperidol are thought to exert Address for correspondence : J.-M. Beaulieu, 487 CARL Building, Box 3287, Duke University Medical Center, Durham, NC 27710, USA. Tel. : (919) 684-6094 Fax : (919) 681-8641 E-mail : [email protected].