MAP Kinase Cascade

MAP kinases are abundantly present in brain and have been postulated to play a major role in a variety of long-term CNS functions, in both the developing and the mature CNS (Fukunaga and Miyamoto 1998; Kornhauser and Greenberg 1997; Matsubara et al. 1996; Robinson et al. 1998). With respect to their actions in the mature CNS, MAP kinases have been implicated in mediating neurochemical processes associated with long-term facilitation (Martin et al. 1997), long-term potentiation (English and Sweatt 1996, 1997), associative learning (Atkins et al. 1998), one-trial and multitrial classical conditioning (Crow et al. 1998), long-term spatial memory (Blum et al. 1999), and modulation of the addictive effects of abused drugs (Lu et al. 2005). They have also been postulated to integrate information from multiple infrequent bursts of synaptic activity (Murphy et al. 1994). Importantly for the present discussion, MAP kinase pathways have been demonstrated to regulate the responses to environmental stimuli and stressors in rodents (Xu et al. 1997) and to couple PKA and PKC to CREB protein phosphorylation in area CA1 of the hippocampus (Roberson et al. 1996, 1999). These studies suggest the possibility of a broad role for the MAP kinase cascade in regulating gene expression in long-term forms of synaptic plasticity (Roberson et al. 1999). For example, it has recently been shown that CREB modulates excitability of neurons of the nucleus accumbens, which helps to limit behavioral sensitivity to cocaine in rodent models (Dong et al. 2006). Thus, overall, the data suggest that MAP kinases play important physiological roles in the mature CNS and, furthermore, may be important targets for the actions of CNS-active agents (Nestler 1998).

Growth factors acting through specific receptors (e.g., BDNF acting on TrkB) activate the Ras/MAP kinase signaling cascade (Figure 1-15). Among the targets of the MAP kinase pathway is ribosomal S6 kinase (RSK). RSK phosphorylates CREB and other transcription factors. Studies have demonstrated that the activation of the MAP kinase pathway can inhibit apoptosis by inducing the phosphorylation and inactivation of the pro-apoptotic protein BAD (Bcl-xl/Bcl-2-associated death promoter) and increasing the expression of the anti-apoptotic protein Bcl-2 (the latter effect likely involves CREB) (Bonni et al. 1999; Riccio et al. 1997). Phosphorylation of BAD occurs via activation of RSK. RSK phosphorylates BAD and thereby promotes its inactivation. Activation of RSK also mediates the actions of the MAP kinase cascade and neurotrophic factors on the expression of Bcl-2. RSK can phosphorylate CREB, leading to the expression of genes with neurotrophic functions, such as Bcl-2 and BDNF (see Figure 1-15). Treatment with mood-stabilizing drugs activates the ERK (extracellular signal-related kinase) pathway in brain regions involved in mood regulation (reviewed in G. Chen and Manji 2006). Earlier work showed that lithium and valproate induce AP-1 and CREB transcription factors and enhance expression of the bcl-2 gene. Later, it was found that chronic lithium or valproate treatment promotes neurogenesis in the hippocampus, an effect mediated at least in part by activation of the ERK pathway (see G. Chen and Manji 2006).

FIGURE 1-15. MAP (mitogen-activated protein) kinase signaling pathway.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

The influence of neurotrophic factors on cell survival is mediated by activation of the MAP kinase cascade and other neurotrophic cascades. Activation of neurotrophic factor receptors referred to as tyrosine receptor kinases (Trks) results in activation of the MAP kinase cascade via several intermediate steps, including phosphorylation of the adaptor protein Shc and recruitment of the guanine nucleotide exchange factor Sos. This results in activation of the small guanosine triphosphate-binding protein Ras, which leads to activation of a cascade of serine/threonine kinases. This includes Raf, MAP kinase kinase (MEK), and MAP kinase (also referred to as extracellular response kinase, or ERK). One target of the MAP kinase cascade is the ribosomal S6 kinases, known as RSK, which influences cell survival in at least two ways. RSK phosphorylates and inactivates the pro-apoptotic factor BAD (Bcl-xl/Bcl-2-associated death promoter). RSK also phosphorylates cAMP response element-binding protein (CREB) and thereby increases the expression of the anti-apoptotic factor Bcl-2 and brain-derived neurotrophic factor (BDNF). Ras also activates the phosphoinositol-3 kinase (PI3K) pathway, a primary target of which is the enzyme glycogen synthase kinase (GSK-3). Activation of the PI3 kinase pathway deactivates GSK-3. GSK-3 has multiple targets in cells, including transcription factors (3-catenin and c-Jun) and cytoskeletal elements such astau. Many of the targets of GSK-3 are pro-apoptotic when activated. Thus, deactivation of GSK-3 via activation of the PI3K pathway results in neurotrophic effects. Lithium inhibits GSK-3, an effect that may be, at least in part, responsible for lithium's therapeutic effects. These mechanisms underlie many of the long-term effects of neurotrophins, including neurite outgrowth, cytoskeletal remodeling, and cell survival.

Source. Adapted from Gould TD, Chen G, Manji HK: "Mood Stabilizer Psychopharmacology." Clinical Neuroscience Research 2:193-212, 2002. Copyright 2002, Elsevier. Used with permission.

Inactivation of the ERK pathway in the CNS induces animal behavioral alterations reminiscent of manic symptoms, which are likely to depend on ERK's effect on distinct brain regions and the presence of interacting molecules (Shaltiel et al. 2007). Moreover, ERK knockout mice display behavioral abnormalities related to manic symptoms. These data support a clinical role for the ERK pathway in therapeutic action of mood stabilizers. Nevertheless, the possible role of this pathway in the pathophysiology of bipolar disorder has yet to be elucidated.

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