Signal Transduction Pathways

Signal transduction refers to the processes by which extracellular stimuli are transferred to—and propagated as—intracellular signals (Figure 1-11). Multicomponent cellular-signaling pathways interact at various levels, thereby forming complex networks that allow the cell to receive, process, and respond to information (Bhalla and Iyengar 1999; Bourne and Nicoll 1993). These networks facilitate the integration of signals across multiple time scales, the generation of distinct outputs that depend on input strength and duration, and the regulation of intricate feed-forward and feedback loops (Bhalla and Iyengar 1999). These properties of signaling networks suggest that they play critical roles in cellular memory; thus, cells with different histories, and therefore expressing different repertoires of signaling molecules, interacting at different levels, may respond quite differently to the same signal over time. Given their widespread and crucial role in the integration, regulation, amplification, and fine-tuning of physiological processes, it is not surprising that abnormalities in signaling pathways have now been identified in a variety of human diseases (Simonds 2003; Spiegel 1998). Pertinent to the present discussion is the observation that a variety of diseases manifest a relatively circumscribed symptomatology, despite the widespread, often ubiquitous expression of the affected signaling proteins.

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.

Although complex signaling networks are likely present in all eukaryotic cells and control various metabolic, humoral, and developmental functions, they may be especially important in the CNS, where they serve the critical roles of first amplifying and "weighting" numerous extracellularly generated neuronal signals and then transmitting these integrated signals to effectors, thereby forming the basis for a complex information-processing network (Bourne and Nicoll 1993; Manji 1992). The high degree of complexity generated by these signaling networks may be one mechanism by which neurons acquire the flexibility for generating the wide range of responses observed in the nervous system. These pathways are thus undoubtedly involved in regulating such diverse vegetative functions as mood, appetite, and wakefulness and are therefore likely to be involved in the pathophysiology of a variety of psychiatric disorders and their treatments.

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