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FIGURE 1–11. Principles of signal transduction.As described in the text, neurons regulate signaling pathways through multiple mechanisms and at multiple levels. Neuronal circuits possess a large number of extracellular neuroactive molecules (1; labeled A, B, and C) that can interact with multiple receptors (2). Binding of neuroactive molecules to receptors can result in stimulation and/or attenuation of multiple cellular signaling pathways (3), depending on the type of receptor, location in the central nervous system, and activity of other signaling pathways within the cell. Thus, the potential is there to greatly amplify the signals. This signaling can then converge on one signaling pathway (4) or diverge into many signaling pathways (5). Activation of signaling pathways alters gene transcription and activity of proteins such as ion channels and other signaling molecules (6). Additionally, activation of signaling pathways can both positively (7) and negatively (8) regulate the function of extracellular receptors. Bcl-2 = an anti-apoptotic protein; BDNF = brain-derived neurotrophic factor; CREB = cAMP response element–binding protein.

FIGURE 1–12. cAMP signaling pathway.Receptors can be positively (e.g., -adrenergic, D1) or negatively (e.g., 5-HT1A, D2) coupled to adenylyl cyclase (AC) to regulate cAMP levels. The effects of cAMP are mediated largely by activation of protein kinase A (PKA). One major downstream target of PKA is CREB (cAMP response element–binding protein). After activation, the phosphorylated CREB binds to the cAMP response element (CRE), a gene sequence found in the promoter of certain genes; data suggest that antidepressants may activate CREB, thereby bringing about increased expression of a major target gene, BDNF. Phosphodiesterase is an enzyme that breaks down cAMP to AMP. Some antidepressant treatments have been found to upregulate phosphodiesterase. Drugs like rolipram, which inhibit phosphodiesterase, may be useful as adjunct treatments for depression. Forskolin is an agent used in preclinical research to stimulate adenylyl cyclase.

FIGURE 1–13. Phosphoinositide (PI) signaling pathway.A number of receptors in the CNS (including M1, M3, M5, 5-HT2C) are coupled, via Gq/11, to activation of PI hydrolysis. Activation of these receptors induces phospholipase C (PLC) hydrolysis of phosphoinositide-4,5-bisphosphate (PIP2) to sn-1,2-diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). DAG activates protein kinase C (PKC), an enzyme that has many effects, including the activation of phospholipase A2 (PLA2), an activator of arachidonic acid signaling pathways. IP3 binds to the IP3 receptor, which results in the release of intracellular calcium from intracellular stores, most notably the endoplasmic reticulum. Calcium is an important signaling molecule and initiates a number of downstream effects such as activation of calmodulins and calmodulin-dependent protein kinases (see Figure 1–15). IP3 is recycled back to PIP2 by the enzymes inositol monophosphatase (IMPase) and inositol polyphosphatase (IPPase; not shown), both of which are targets of lithium. Thus, lithium may initiate many of its therapeutic effects by inhibiting these enzymes, thereby bringing about a cascade of downstream effects involving PKC and gene expression changes.Source. Adapted from Gould TD, Chen G, Manji HK: "Mood Stabilizer Pharmacology." Clinical Neuroscience Research 2:193–212, 2003. Copyright 2003, Elsevier. Used with permission.

FIGURE 1–14. Calcium-mediated signaling.In neurons, Ca2+-dependent processes represent an intrinsic nonsynaptic feedback system that provides competence for adaptation to different functional tasks. Ca2+ is generally mobilized in one of two ways in the cells: either by mobilization from intracellular stores (e.g., from the endoplasmic reticulum) or from outside of the cell via plasma membrane ion channels and certain receptors (e.g., NMDA [N-methyl-d-aspartate]). The external concentration of Ca2+ is approximately 2 mM, yet resting intracellular Ca2+ concentrations are in the range of 100 nM (2 x 104 lower). Local high levels of calcium result in activation of enzymes, signaling cascades, and, at extremes, cell death. Release of intracellular stores of calcium is primarily regulated by inositol-1,4,5-triphosphate (IP3) receptors that are activated upon generation of IP3 by phospholipase C (PLC) activity, and the ryanodine receptor that is activated by the drug ryanodine. Many proteins bind Ca2+ and are classified as either "buffering" or "triggering." These include calcium pumps, calbindin, calsequestrin, calmodulin, PKC, phospholipase A2, and calcineurin. Once stability of intracellular calcium is accomplished, transient low-magnitude changes can serve an important signaling function. Calcium action is local. Because of the high concentration of calcium-binding proteins, it is estimated that the free Ca2+ ion diffuses only approximately 0.5 M and is free for about 50 sec before encountering a Ca2+-binding protein. Ca2+ is sequestered in the endoplasmic reticulum (which serves as a vast web and framework for Ca2+-binding proteins to capture and sequester Ca2+). Ca2+ buffering/triggering proteins are nonuniformly distributed, so there is considerable subcellular variation of Ca2+ concentrations (e.g., near a Ca2+ channel). The primary mechanism for Ca2+ calcium exit from the cell is either via sodium-calcium exchange or by means of a calcium pump.

FIGURE 1–15. MAP (mitogen-activated protein) kinase signaling pathway.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 (-catenin and c-Jun) and cytoskeletal elements such as tau. 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.


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