Aside from direct interactions that were described in the previous sections, ion channels also undergo extensive modulation by processes that link them indirectly to G proteins. In this respect, a hallmark feature of signalling pathways involving GPCRs is the production of cytosolic second messengers. The enormous power of these receptors to influence so many diverse reactions inside any given cell derives in large part from their ability to stimulate enzymes that respond to changes in the concentrations of compounds such as cAMP or cGMP (Chapter 5). Few proteins are resistant to the widespread consequences of phosphory-lation or dephosphorylation that occur in response to many G protein-linked signals, and the series of events that originate in one area of the cell can often influence the activities of proteins found great distances away in separate locations. This allows channels to be connected to a much larger network of regulatory machinery and thereby greatly enhances their ability to be precisely tuned by external signals. Responses involving the indirect actions of second messengers generally tend to be longer lasting and also somewhat slower than direct routes. Ion channels that are targeted by these pathways will therefore often alter membrane excitability over more prolonged periods of time.
In addition to the minimal criteria that are required to establish a link between G proteins and ion channels, indirect pathways predict that any observed changes in channel activity should be replicated by the addition of the relevant enzyme or second messenger itself in the absence of G proteins. Though many tools are now available for bypassing the G protein activation step to cause changes in the levels of various second messengers, progress is at times hampered by the technical difficulties associated with such experiments. Furthermore, the use of pharmacological drugs to activate or inhibit the actions of specific enzymes is often confounded by the nonselective nature of their effects. Nonetheless, these compounds continue to serve as invaluable tools in trying to reconstruct the transduction pathways that connect G protein-linked receptors with certain ion channels. It is beyond the scope of this chapter to provide an extensive review of all second messenger pathways involved in channel modulation. Instead, we will describe selected examples of well-characterized enzymes and second messengers frequently implicated in the regulation of channel activity. Table 6.1 lists some further examples of ion channels that are affected by such pathways.
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