Extracellular second messengersa contradiction in terms

A final point of interest is that although by definition second messengers are intracellular, microdialysis and other studies have succeeded in measuring both cAMP and inositol-1,4,5-trisphosphate in the brain extracellular space. These extracellular pools of second messengers are sensitive to pharmacological manipulation, with the levels being increased by the agents that elevate their intracellular concentrations. Thus, Lazareno et al. (16> found that dopamine increased cAMP levels both in slices of rat striatum and in the incubation medium, while Egawa et al.(17> showed that the increases in extracellular cAMP produced by adding noradrenaline to rat cortical slices were equivalent to those obtained intracellularly, and furthermore that infusion of noradrenaline via a microdialysis probe implanted in the cortex produced a dose-dependent increase in cAMP. Similarly, inositol-1,4,5-trisphosphate formation in rat hippocampal microdialysate was stimulated by carbachol and inhibited by the muscarinic antagonist pirenzepine. (!8>

A fascinating question concerns the role of these extracellular second messengers. The discovery by Gilman's group of the structure of the adenylate cyclase molecule and its similarity to membrane transporters suggested that adenylate cyclase itself may form a channel for cAMP efflux and that cAMP may therefore function as an intercellular signal. One possibility is that extracellular cAMP is converted to the transmitter substance adenosine, which has several important actions on neurones including inhibition of glutamate release and activation of potassium channels. Pull and Mcllwain (19> found as early as 1977 that electrical stimulation of 14C-adenine-labelled slices induced release of cAMP into extracellular fluid, and that extracellular adenosine derived from this cAMP.

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