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Intraneuronal Signaling Pathways

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  1. Introduction
  2. Intraneuronal signaling pathways
  3. The concept of neurons or networks of neurons
  4. Major signaling pathways
    1. Neurotransmitter receptors
    2. Cyclic AMP
    3. Cyclic GMP
    4. Phosphoinositide (PI)
    5. Direct coupling between G proteins and ion channels
    6. Tyrosine phosphorylation
  5. Cross talk among signaling pathways
  6. Conclusion
  7. References

Prior to delineating the organization of specific intraneuronal signaling pathways, it is important to consider, in general terms, their role in helping neurons interpret and respond to the barrage of afferent stimulation impinging on them continuously. From an evolutionary perspective, second messenger systems predate neurotransmitters and neurotrophins, examples of first messengers detected by cell surface receptors. Before the advent of neurotransmitters, prokaryotic organisms relied on cyclic adenosine monophosphate (cAMP) and other intracellular signaling pathways to coordinate diverse responses located in disparate parts of these unicellular organisms to changes in ambient nutrients or conditions. Neurotransmitters and neurotrophins have evolved subsequently to take advantage of these internal signaling pathways that have undergone a parallel growth process.

[...] As a result of cross-talk between systems, coordinate activation of multiple pathways can have important synergistic effects. Another level of cross-talk has been observed at the level of specific target proteins. Rather than being substrates for specific kinases, the more common situation is that a given target is phosphorylated by multiple kinases. This overlapping of substrate specificity allows for complex patterns of regulation. For example, phosphorylation of a specific substrate by both protein kinase A and protein kinase C may have qualitatively different effects than modification by either alone. [...]

[...] Neurotransmitter receptors may couple to adenylate cyclase via different classes of G proteins, referred to as Gs or Gi, depending on whether they stimulate or inhibit cyclic AMP formation. In this way, the net effect of the transmitter on a given neuron is determined by the specific receptor subtypes expressed on its surface. For example, norepinephrine stimulates adenylate cyclase via its interaction with b-adrenergic receptors, the type that speed heart rate, and it inhibits adenylate cyclase via the muscarinic cholinergic receptor subtype. [...]

[...] Second, the ability of multiple adapter proteins to interact with the activated cytoplasmic tail of tyrosine kinase receptors confers a remarkable degree of divergence as multiple signaling pathways can be engaged simultaneously. Thus, the importance of tyrosine phosphorylation signaling does not reside simply in the availability of another residue that is amenable to modification by phosphorylation; rather, it represents an intracellular signaling system built on an alternative set of architectural principles. Identification of the signaling pathway downstream of Ras has opened up a new avenue to understanding the mechanism of action of growth factors and neurotransmitters. [...]

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