Lotrich and Pollock Protein phosphatases Multiple protein phosphatases (PPs) are present in the brain to dephosphorylate proteins, reversing the effect of kinases (Price and Mumbly 1999). One example is PP1 which has at least three isoforms expressed in the brain (da Cruz e Silva et al 1995). Interaction with spinophilin results in localization of PP1 to the dendritic spines, while interaction with tau bridges PP1 to microtubules (Allen et al 1997). In dendritic spines, PP1 can dephosphorylate CAMKII and glutamate receptors (Kennedy 1998), and PP1 activity may be necessary for effects of 5-HT in acutely affecting prefrontal cortical neuronal activity (Cai et al 2002). There are also genes for several associated regulatory proteins. For example, DARRP-32, whose involvement in potentially affecting SSRI response was discussed above, is a regulator of PP1 (Svenningsson et al 2002). A second phosphatase, PP2A, exists as a heterotrimer, with a catalytic, regulatory, and scaffolding subunit. Both the catalytic and scaffolding subunits exist throughout the brain, and there are several region-specific regulatory subunits (Stack et al 1998). In addition to other activities, PP2A can exist in close relationship with the SERT protein and is involved in regulating SERT’s activity (Bauman et al 2000). PP2B, also known as calcineurin, exists throughout the brain but is particularly enriched in hippocampal dendritic spines. It is activated by calcium/calmodulin (Klee et al 1998). Through the calcium/calmodulin/PP2B pathway, 5-HT2 receptor activation can inhibit calcium channels in the prefrontal cortex (Day et al 2002). However, along with several other PPs in the brain (PP2C, PP4, PP5, PP6) (Cohen 1997), a function in potentially modulating SSRI-induced intracellular transduction remains to be determined. Regulatory and scaffolding proteins Notably many of these intracellular transduction pathways interact in complex ways, depending on the intracellular compartment and association of other regulatory proteins (Sim and Scott 1999; Robinson-White and Stratakis 2002). In addition to the proteins discussed above, others may indirectly play roles. There are multiple regulators of G- protein signaling (RGS) (Chidiac and Roy 2003) that directly modulate G-protein function; multiple receptors for activated PKC (RACKs) that may be important for translocation of PKC to specific intracellular locations; and multiple anchoring proteins that can regulate the location, function, and interaction of various protein kinases (Scott 1997; Bayer and Schulman 2001). As just one example, A- kinase anchoring protein 79/150 (AKAP79/150) is an anchoring protein that interacts with PKA, PKC, and PP2B. It can recruit these three enzymes to glutamate receptors in the dendritic spine via an interaction with membrane- associated guanylate kinase scaffold proteins. Conversely, the activity of AKAP79/150 is regulated by PKC and calmodulin (Gomez et al 2002). To briefly review, there is accumulating evidence in support of several protein kinases, protein phosphatases, and other related second messengers in mediating the effects of SSRIs. Importantly, there is also accumulating initial evidence in support of proximal, intracellular pathway polymorphisms affecting SSRI efficacy. However, for most of these proteins, the association of genetic variation and variable response to SSRIs has yet to be fully investigated. Moreover, chronic administration of SSRIs can also affect various systems that are downstream from these intracellular transduction pathways. Several of these systems have been implicated in depression, as briefly outlined in the next sections, and may offer biologically plausible candidates for association analyses of SSRI response. Hypothalamic-pituitary-adrenal axis Stress and dysregulation of the hypothalamic-pituitary- adrenal (HPA) axis has long been associated with depression (Gold et al 1988; Gold and Chrousos 2002; Strohle and Holsboer 2003), and CRH antagonists may have antidepressant properties (Kunzel et al 2003). Because antidepressants can increase glucocorticoid receptor (GR) expression and potentially normalize the HPA axis, this has been proposed as one mechanism of action (Barden et al 1995; Holsboer 2000; Herr et al 2003). Antidepressants also can alter the synthesis and release of CRH, thereby normalizing the HPA axis (Brady et al 1991; Torres et al 1998). Consistent with this, polymorphisms in the CRH gene that affect cortisol secretion (Rosmond et al 2001) have been described (Gonzalez-Gay et al 2003), and may be associated with major depression (Claes et al 2003) as assessed using haplotype analyses. An initial investigation of a CRH receptor 2 poly- morphism (G1047A) also hinted at a possible role in mood disorders (Villafuerte et al 2002). Polymorphisms in GR have been associated with obesity (Di Blasio et al 2003), sensitivity to dexamethasone challenges (Huizenga et al 1998), and possibly to abnormal responses to stress (DeRijk 24 Neuropsychiatric Disease and Treatment 2005:1(1)