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. [...]
[...] These examples underscore the direct relevance of intraneuronal signaling pathways to the most challenging problems facing psychiatry. Although the overwhelming majority of psychiatric drugs target extracellular receptors or uptake sites, the explosion of information on intraneuronal signaling pathways suggests that these may represent suitable drug targets. In particular, the availability of transgenic approaches to examine the phenotype caused by deleting a specific component of a signaling pathway will be invaluable in developing a new generation of psychiatric drugs aimed at signaling pathways that function beneath the neuronal surface. [...]
[...] However, diffusible second messengers are not universal components of the signaling pathways that mediate the actions of G–protein–coupled neurotransmitter receptors. In many important situations, the G proteins themselves link neurotransmitter receptor activation to ion channels shortcircuiting the rest of the cascade. Prominent examples of this type of arrangement are provided by opioid receptors and muscarinic receptors involved in vagal slowing of the heart. As these receptors had been shown to be linked to Gi and cause inhibition of adenylate cyclase, it had been taken for granted their important effects on ion channel regulation, in particular opening of potassium channels causing hyperpolarization, was a result of lowering cAMP concentrations. [...]
[...] Thus, the discovery of nitric oxide as a neuronal messenger breaches the classical notion that synapses convey information in only one direction. Recent studies have also suggested that another diffusible gas, carbon monoxide, which is also capable of activating guanylate cyclase, may also function in an analogous fashion to nitric oxide. Phosphoinositide Characterization of the neurotransmitter receptors coupled to the cAMP system revealed that there were many receptors that did not act via this second messenger pathway. This discrepancy generated interest in the possible existence of other second messenger systems operating in parallel with the cAMP system. [...]
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