Any of the specialized molecular pathways in the cell that decode extracellular signals and convert the information into cellular response

Intracellular signal transduction cascades (Tr-nsducere, Latin for 'to transfer'), also termed 'signalling pathways', are intracellular molecular pathways that decode and distribute within the cell specific information conveyed by distinct extracellular "stimuli, such as hormones, growth factors, and "neurotransmitters. (Special types of signal transduction cascades are activated by sensory stimuli in specialized sensory receptor cells, but they will not be further discussed here.) Intracellular signal transduction cascades span multiple cellular compartments, from the cell membrane via the cytoplasm to the nucleus. They are ubiquitous in all species and tissues, and involved in all aspects of cellular life, from differentiation and proliferation, via "homeostasis and "plasticity, to death.

The information in intracellular signal transduction cascades flows from transmembrane "receptor(s) to "systems of interacting enzymes and regulatory proteins, which are linked to each other by adaptor and scaffold proteins to provide the right signal channelling (Koch et al. 1991; Niethammer et al. 1996; Whitmarsh et al. 1998). Specific nodes in these cascades are linked via smaller diffusable substances such as cyclic adenosine-3',5'-monophosphate (cAMP), "calcium, inositol triphosphate, or eicosanoids (a family of lipid molecules), whose level is modulated following the stimulus-receptor interaction. These substances distribute and markedly amplify the message. They are termed 'second messengers', as opposed to the 'first messengers' which are the extracellular stimuli (Sutherland et al. 1965). About 20 families of intra-cellular signal transduction cascades have been identified so far. For a tiny selection, to be used merely as an appetizer or an entry point to the intricate world of intracellular signalling cascades, see Cantley et al. (1991), Berridge (1993), Hunter (1995), and Seger and Krebs (1995). Furthermore, in real life signalling pathways are intimately interwoven into complex networks (Figure 39) (Weng et al. 1999), to the point were their "taxonomy looks like a heroic feat.

The first intracellular signal transduction cascade to be identified was the 'cAMP cascade'. This was during the biochemical revolution that has swept biology in the mid-twentieth century (Sutherland and Rall 1960). It so happened that the same cascade was also later identified as critical for neuronal plasticity mechanisms that are engaged in "development and memory. A few words about the cAMP cascade can therefore illustrate not only the operation of signalling pathways in general, but also their role in neuronal plasticity in particular. Hormones or neurotransmitters that regulate the cAMP cascade, such as catecholamines (e.g. "noradrenaline), do so by binding to specific transmembrane receptors coupled, via a detachable transducer called G-protein (Knall and Johnson 1998), to the enzyme adenylyl cyclase. This enzyme produces cAMP (Sunahara et al. 1996; Tesmer et al. 1999). Depending on the specific type of G-protein, the level of cAMP in the cell increases or decreases in response to the stimulus. Before it is degraded by the enzyme cAMP-phosphodiesterase, cAMP activates the cAMP-dependent "protein kinase (PKA). It does so by dissociating the inhibitory regulatory subunits from the catalytic subunits of the enzyme. The latter alter target proteins in the cytoplasm and in the nucleus, by phos-phorylation, which is the addition of a phosphoryl moiety to proteins (phosphorylation is a ubiquitous 'modifying tool' of intracellular signal transduction cascades). Some of the modified proteins are other enzymes, others are signalling and regulatory molecules, still others are transcription factors,1 which modulate gene expression.

There are at least two identified mechanisms by which the cAMP cascade can itself sustain information over time, hence serving as a cellular 'information storage' device and potentially contributing to the "persistence of experience-dependent modifications in neuronal circuits. One involves the experience-dependent degradation of the regulatory subunit of

Fig.39 Intracellular signal transduction cascades convey extracellular information from the cell membrane to the cytoplasm and the nucleus.They interact to form complex signalling networks, whose spatiotemporal pattern of activity at any given points in time controls cellular function. Intracellular signalling cascades in neurons subserve the 'acquisition, 'consolidation, 'persistence (at least in the short-term), and 'retrieval of memory.This highly simplified scheme depicts the information flow and the interactions of only a few cascades. Selected acronyms: AC, adenylate cyclase, the enzyme that produces cAMP;AMPAR, NMDAR, mGluR, types of 'glutamateric 'receptors; PAR, ^-adrenergic receptor; 3y,Gqa,Gsa, subunits of G-proteins; BDNF, brain-derived neurotrophic factor, which is a growth factor; CaM, calmodulin, a 'calcium-binding protein; CaMK, calcium/calmodulin 'protein kinase; 'CREB, Elk-1 — transcription factors; Glu, 'glutamate; GRB, growth factor-binding protein; MAPK, mitogen-activated protein kinase; NA, noradrenaline; PLC, the enzyme phospholipase C; PKA, protein kinase A; PKC, protein kinase C; Ras, a small G protein; RTK, receptor tyrosine protein kinase. The spike pattern above the membrane on the upper right-hand side represents electrical activity. (Adapted from Weng et al. 1999.)

Extracellular stimuli

Fig.39 Intracellular signal transduction cascades convey extracellular information from the cell membrane to the cytoplasm and the nucleus.They interact to form complex signalling networks, whose spatiotemporal pattern of activity at any given points in time controls cellular function. Intracellular signalling cascades in neurons subserve the 'acquisition, 'consolidation, 'persistence (at least in the short-term), and 'retrieval of memory.This highly simplified scheme depicts the information flow and the interactions of only a few cascades. Selected acronyms: AC, adenylate cyclase, the enzyme that produces cAMP;AMPAR, NMDAR, mGluR, types of 'glutamateric 'receptors; PAR, ^-adrenergic receptor; 3y,Gqa,Gsa, subunits of G-proteins; BDNF, brain-derived neurotrophic factor, which is a growth factor; CaM, calmodulin, a 'calcium-binding protein; CaMK, calcium/calmodulin 'protein kinase; 'CREB, Elk-1 — transcription factors; Glu, 'glutamate; GRB, growth factor-binding protein; MAPK, mitogen-activated protein kinase; NA, noradrenaline; PLC, the enzyme phospholipase C; PKA, protein kinase A; PKC, protein kinase C; Ras, a small G protein; RTK, receptor tyrosine protein kinase. The spike pattern above the membrane on the upper right-hand side represents electrical activity. (Adapted from Weng et al. 1999.)

PKA, which results in an increase in the availability of the free, active catalytic subunits. This mechanism has been specifically implicated in memory in conditioning of defensive reflexes in "Aplysia (Chain et al. 1999). The other mechanism involves modulation of gene expression ("immediate early genes). A most prominent substrate of PKA in this case is "CREB, which in many systems is instrumental in switching on the long-term "phase of neuronal plasticity ("Aplysia, "long-term potentiation). CREB itself is a substrate for multiple signalling pathways. cAMP also regulates certain proteins in a PKA-independent manner (Kawasaki et al. 1998). All in all, stimulus-induced modulation of the cAMP cascade results in multiple molecular modifications, some of which involve existing proteins, others the synthesis of new ones.

Research on the role of intracellular signal transduc-tion cascades in plasticity, learning, and memory is overwhelmingly rich (for only a few selected examples, see Thomas et al. 1994; Byrne and Kandel 1996; Deisseroth et al. 1996; Kornhauser and Greenberg 1997; Berman et al. 1998). It is useful, though, to focus on a few generalizations:

1. Intracellular signal transduction cascades encode at the cellular "level facets of the internal representations of neurons and neuronal circuits. In the not-yet-available "reductive theories of memory, values representing spatiotemporal patterns of activity of signalling pathways will probably be terms in the 'laws' that "bind representational events at the different levels of operation of the brain (see also 3 below). We do not yet know, however, which parameters of signalling pathways are critical for computations and representations by neurons and neuronal circuits. Such parameters may not necessarily be the mere level of a second messenger, or the activity of a key enzyme in the cascade (e.g. Barkai and Leibler 1997).

2. The spatial and temporal complexity of intracellular signal transduction cascades contributes to the representational and computational repertoire of neurons and hence probably also of neuronal circuits. The combinatorial interaction between cascades increases the intracellular complexity while providing additional options for signalling specificity (e.g. Madhani and Fink 1998; Crabtree 1999; Weng et al. 1999). All this also implies that the idea that reduction culminates in simplification is a myth. As every cellular biologist knows, the more we understand the inner working of a cell, the more we complicate life.

3. Intracellular signal transduction cascades couple multiple temporal domains in the nervous system: they respond to transient biophysical events, occurring at the millisecond range, by inducing biochemical change that last much longer (Dudai 1997b; "calcium). They are therefore expected to be instrumental in subserving the transformation of "percepts into "engrams.

4. Intracellular signal transduction cascades provide multiple loci of integration for information stemming from different extracellular stimuli. They are therefore candidate 'associative devices' in biological learning machines (Dudai 1994a; "coincidence detector).

5. Intracellular signal transduction cascades implement transitions from short- to long-term plasticity in the process of memory "consolidation. They are therefore candidate 'consolidation devices' in biological learning machines (ibid.).

6. Intracellular signal transduction cascades retain information over time by becoming "persistently active long after the activating stimulus had dissipated. They are therefore candidate 'information storage devices' in biological learning machines, at least in the context of short-term memory (ibid.).

Bearing all the above in mind, we should still note that, although every neurotransmitter or hormone is expected to modulate the activity of some intracellular signal transduction cascades in its neuronal target, it does not follow that the ensuing cellular alterations are necessarily relevant to learning. Whether they do or not depends on whether the neuronal modifications culminate in a representational change in the neuron and in the neuronal circuit. Lasting modulation of signal transduc-tion cascades is hence always relevant to neuronal maintenance and plasticity, but only sometimes to memory.

Selected associations: Acquisition, Consolidation, Coincidence detector, Receptor, Reduction

1For what transcription factors are,see *CREB, 'immediate early genes.

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