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Although inositol phospholipids are relatively minor components of cell membranes, they play a major role in receptor-mediated signal transduction pathways. They are involved in a diverse range of responses, such as cell division, secretion, and neuronal excitability and responsiveness. In many cases, Gq/11 is involved, and it is believed that Gq/11 directly binds to and activates phospholipase C (Figure 1–13). In other cases, however, it is the subunits released upon activation of receptors coupled to Gi/Go that bring about activation of the enzyme PLC to produce the intracellular second messengers sn-1,2-diacylglycerol (DAG; an endogenous activator of PKC) and inositol-1,4,5-triphosphate (IP3). IP3 binds to the IP3 receptor and facilitates the release of calcium from intracellular stores, in particular the endoplasmic reticulum (see Figure 1–13). The released calcium then interacts with various proteins in the cell, including the important family of calmodulins (Ca2+-receptor protein calmodulin, or CaM) (discussed later in this chapter; Figure 1–14). Calmodulins then activate calmodulin-dependent protein kinases (CaMKs), which affect the activity of diverse proteins, including ion channels, signaling molecules, proteins that regulate apoptosis, scaffolding proteins, and transcription factors (Miller 1991; Soderling 2000).

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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.

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