Lotrich and Pollock that has been associated with major depression (Zill et al 2002). As this subunit is expressed in many areas of the body, this polymorphism has also been associated with other disorders including hypertension, which may be comorbid with major depression (Jia et al 1999; Abe et al 2002). The expression of αs is increased by SSRI treatment (Lesch et al 1992). Polymorphisms in the G protein β3 subunit, which is expressed in the brain, have also been associated with both depression and cardiovascular disease (Bondy et al 2002; Zill et al 2002; Nurnberger et al 2003). Moreover, preliminary evidence supports a role for this polymorphism (C825T) in response to antidepressant treatment (Zill et al 2002; Serretti et al 2003), including SSRIs. The αi subunits, which mediate the effects of 5-HT1 receptors, have several isoforms expressed in the brain (Downes and Gautam 1999) and have been implicated in antidepressant response in mouse models (Galeotti et al 2002). Adenylyl cyclases, protein kinases, phospholipases, and phosphodiesterases Both the αs and αi G protein subunits directly affect the function of adenylyl cyclase (AC), resulting in either increased or decreased cyclic adenosine monophosphate (cAMP), respectively. There are at least 9 genes encoding 9 different AC enzymes. Most are expressed in the brain, although subtypes 1, 2, 6, 8, and 9 are more predominantly so (Defer et al 2000). Antidepressant treatment, including SSRIs, has been associated with increased transcription of AC1 (Jensen et al 2000). 5-HT1a activation decreases activity of neuronal AC2 (Albert et al 1999), and mice lacking AC8 exhibit altered stress-induced anxiety (Schaefer et al 2000). Each of these varied findings hints at a role for various AC isozymes in mediating the antidepressant effects of SSRIs. Initial studies of AC7 and AC9 polymorphisms have been performed, although these particular isoforms did not demonstrate an association with depression (Hellevuo et al 1997; Toyota et al 2002). Adenylyl cyclase activity increases cAMP, which then binds to PKA. PKA is a tetramer containing two regulatory (R) subunits and two catalytic (C) subunits. Type II PKA is predominantly expressed in the brain. Activation by cAMP results in dissociation of the R and C subunits, allowing the C subunit to phosphorylate multiple substrates – including but not limited to the b-adrenergic receptor, the nicotinic acetylcholine receptor, sodium and calcium channels, N- methyl-D-aspartate (NMDA) receptor subunits, tyrosine hydroxylase, neurofilaments, microtubule associated protein 2 (MAP2), synapsin I, rabphilin, GABA A receptor subunits, SERT, and cAMP response element-binding protein (CREB) (Nibuya et al 1996; Wischmeyer and Karschin 1996). Abnormalities in PKA/CREB signaling have been associated with mood disorders (Shelton et al 1996; Rahman et al 1997; Chang et al 2003; Kohen et al 2003). For example, an increase in phosphorylated CREB was noted in the postmortem prefrontal cortexes of depressed victims of suicide, but only in antidepressant-free subjects (Odagaki et al 2001). Decreased CREB was observed, however, in the temporal cortexes of subjects who had had major depression, but only in antidepressant-free subjects (Dowlatshahi et al 1998). Although the relationship between PKA/CREB and major depression may be complex, antidepressants normalized the CREB measures in both studies. Stimulated by these observations, several theories of SSRI action have hypothesized a primary role for CREB phosphorylation by PKA (Duman et al 1997; Shelton 2000), as reviewed below. However, other phosphorylation events may also be important. For example, in neurons, PKA RIIb (regulatory subunit IIb) mediates association with membranes, where PKA is coupled with MAP2. As noted above, PKA can phosphorylate MAP2, decreasing micro- tubule assembly, and potentially affecting dendritic and synaptic growth (Nestler et al 1989; Miyamoto et al 1997). Chronic SSRI treatment is capable of increasing PKA in select brain areas (Perez et al 1991; Rausch, Gillespie, et al 2002) while decreasing PKA in others (Rosin et al 1995). Additionally, SSRI treatment can result in a translocation of PKA into various intracellular compartments, potentially corresponding to its eventual antidepressant effect (Mori et al 1998). Although abnormalities in PKA activation have been associated with differences in response to noradrenergic antidepressants (Gurguis et al 1999), a systematic study of polymorphisms affecting PKA has not yet been performed. Given the widespread expression of PKA subunits, polymorphisms that drastically affect function may be expected to have widespread deleterious effects (Stergiopoulos and Stratakis 2003). The cAMP produced by adenylyl cyclase is recycled by phosphodiesterases (PDEs). A limited number of the multiple PDE isoforms are expressed in the brain. In particular, PDE4 exists in brain regions involved in mood (Cherry and Davis 1999). Interestingly, PDE4 inhibitors such as rolipram have antidepressant effects. Antidepressants 22 Neuropsychiatric Disease and Treatment 2005:1(1)