PI3 Kinase Akt Pathway

The PI3K-Akt pathway is also particularly important for mediating neuronal survival in a wide variety of circumstances. Trk receptors can activate PI3K through at least two distinct pathways, the relative importance of which differs between neuronal subpopulations. In many neurons, Ras-dependent activation of PI3K is the most important pathway through which neurotrophins promote cell survival (see Figure 1-15). In some cells, however, PI3K can also be activated through three adaptor proteins: Shc, Grb-2, and Gab-1. Binding to phosphorylated tyrosine 490 of Shc results in recruitment of Grb-2 (see Figure 1-9). Phosphorylated Grb-2 provides a docking site for Gab-1, which in turn is bound by PI3K (Brunet et al. 2001). PI3K directly regulates certain cytoplasmic apoptotic pathways. Akt has been proposed to act both prior to the release of cytochrome c by pro-apoptotic Bcl-2 family members and subsequent to the release of cytochrome c by regulating components of the apoptosome. Akt phosphorylates the pro-apoptotic Bcl-2 family member BAD, thereby inhibiting BAD's pro-apoptotic functions (see Figure 1-15) (Datta et al. 1997).

Another important target of Akt is the enzyme glycogen synthase kinase-3 (GSK-3) (see Figures 1-11 and 1-15). GSK-3 is a serine/threonine kinase that is, in general, constitutively active in cells. It is found in two forms— a and D—and currently appears to be the only kinase significantly directly inhibited by lithium (Davies et al. 2000; Klein and Melton 1996; Stambolic et al. 1996). It may thus represent a target of the development of novel medications for the treatment of bipolar disorder (Gould and Manji 2005). While most research has focused on the (?> isoform, available evidence suggests that the two forms may have very similar—though not absolutely identical—biological properties (Ali et al. 2001; Plyte et al. 1992). GSK-3 was named on the basis of its originally described function as a kinase that inactivates glycogen synthase. Following insulin receptor stimulation, PI3K and Akt are activated, and this results in the phosphorylation and concomitant inactivation of GSK-3. Inactivated GSK-3 no longer phosphorylates glycogen synthase, allowing the formation of glycogen from glucose (Cohen and Frame 2001; Woodgett 2001).

In addition to regulation by Akt, other kinases, including p70 S6 kinase, RSK, and cAMP-dependent protein kinase (PKA), appear to deactivate GSK-3 by phosphorylation (Cohen and Frame 2001; Grimes and Jope 2001). The effect of GSK-3 on transcription factors such as c-Jun, heat shock factor-1 (HSF-1), nuclear factor of activated T-cells (NFAT), and [3-catenin (see below) has drawn considerable interest and is particularly noteworthy (Frame and Cohen 2001; Grimes and Jope 2001) (see Figure 1-15). Generally, GSK-3 activity results in suppression of the activity of transcription. Conversely, inactivation of GSK-3 appears to activate these transcription factors (Grimes and Jope 2001). Thus, GSK-3 is well positioned to receive signals from multiple diverse signal pathways, a function that is undoubtedly critical in the CNS.

GSK-3 is also a critical regulator of the Wnt pathway. Wnt is a family of secreted glycoproteins that are well known to have important roles in development.

Signaling through Wnt glycoproteins results in inactivation of GSK-3 and a subsequent increase in the transcription factor (3-catenin. Furthermore, some studies suggest a role for B-catenin (and Wnt) in synaptic plasticity (Salinas 1999; Salinas and Hall 1999). Additional studies have suggested that 3-catenin itself may play an important role for this protein in the function of the brain. Indeed, upregulation of this protein is sufficient to cause the formation of gyri and sulci in the mouse brain, a finding observed only in higher mammals, and is suggestive of an important role in higher mammalian cognitive functions (Chenn and Walsh 2002).

PLC-71 Pathway

Phosphorylated Trk receptors also recruit PLC-71 (see Figure 1-9). The Trk kinase then phosphorylates and activates PLC-71, which acts to hydrolyze phosphatidylinositides to generate DAG and IP3. IP3 induces the release of Ca2+ stores, increasing levels of cytoplasmic Ca2+ and thereby activating many pathways controlled by Ca2+. It has been shown that neurotrophins activate protein kinase C 5, which is required for activation of the ERK cascade and for neurite outgrowth (Patapoutian and Reichardt 2001). As discussed previously, emerging data suggest that the regulation of hippocampal LTP by TrkB

receptors is mediated primarily through the PLC-7 cascade (for details, see Minichiello et al. 2002).

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