Dysregulated signal transduction as therapeutic target in FXS. Shown are signaling pathways and molecules that have proven to be promising targets for therapeutic treatment based on preliminary clinical trials and/or studies in FXS animal models. Targets can be divided into three major groups: (1) membrane receptors such as GABA, mGlu_1/5, and dopamine D_1/5 receptors and their regulator RGS4; (2) the central intracellular signaling molecules ERK1/2 and PI3K; and (3) downstream targets such as MMP-9, mTOR, GSK3β, GRK2, and PAK. Although genetic and pharmacologic studies suggest that these proteins might be promising therapeutic targets, the underlying mechanisms are mostly elusive, with a few exceptions: FMRP was shown to directly regulate PI3K and PIKE mRNA translation, protein expression, and enzymatic activity (indicated by red outlines) (Gross et al, 2010; Sharma et al, 2010). Furthermore, FMRP associates with PAK and GRK2 protein, but the functional consequences of these interactions are unknown (Hayashi et al, 2007; Wang et al, 2008b). Some potential therapeutic targets show dysregulated expression (MMP-9, GABA receptors), subcellular localization (PAK and GRK2), and/or phosphorylation (ERK1/2, GSK3β, PAK, GRK2, mTOR) in the absence of FMRP (highlighted with yellow asterisks), but the detailed mechanisms are unknown and future studies will have to show whether these are the direct effects of loss of FMRP or are caused by dysregulated signaling through other pathways. Yellow triangles mark mGlu receptors and the regulator of G-protein signaling RGS4, which were shown to be promising therapeutic targets, but do not seem to be directly altered by loss of FMRP. Black arrows indicate how upstream membrane receptors activate and/or regulate some of the downstream targets, illustrating crosstalk between pathways and putative shared dysregulated downstream mechanisms: MMP-9 was suggested to be regulated by mGlu_1/5 signaling (Bilousova et al, 2009) and by GABAergic signaling via an ERK-dependent mechanism (Miao et al, 2010). ERK1/2 and PI3K are regulated by mGlu_1/5 (Banko et al, 2006) and by TrkB signaling (Yoshii and Constantine-Paton, 2010). ERK1/2 was shown to signal downstream of D_1/5 (Beaulieu and Gainetdinov, 2011). A study suggests that PI3K signaling might affect GRK2 activity (Banday et al, 2007), which might contribute to the crosstalk between mGlu_1/5 and D_1/5 (Deng et al, 2010). GRK2 was suggested to be involved in dysregulated signaling through D1 receptors in Fmr1 KO mice (Wang et al, 2008b). PI3K can regulate PAK activity via Rac and ERK1/2 itself was shown to be regulated by Rac/PAK signaling (Lim et al, 1996; Welch et al, 2003). GSK3β activity is affected by both ERK1/2 and PI3K, downstream of mGlu_1/5 and D_1/5 (Lebel et al, 2009; Min et al, 2009).