Forskolin-activated cAMP cascade

Iodide by an Xl-type mechanism inhibits both cAMP and the phospholipase G cascades (Figure 32.2). The inhibition of TSH, prostaglandin El (PGEl), cholera toxin and forskolin-activated cAMP cascade bears on Gs— adenylyl cyclase couple and on cAMP generation (Gochaux et al, 1987 Filetti and Rapoport, 1983 ... 

One of the best-characterized effectors and second messenger systems is the cAMP cascade that can be either activated or inhibited by neurotransmit-ter/neuropeptide receptors, including those implicated in anxiety/stress such as CRE Receptors that activate cAMP synthesis couple with the stimulatory G protein, Gsa, and those that inhibit this second messenger couple with the inhibitory G protein, Gia, and these either stimulate or inhibit adenylyl cyclase, the effector enzyme responsible for synthesis of cAMP (Duman and Nestler 1999). There are at least nine different forms of adenylyl cyclase that have been identified by molecular cloning, each with a unique distribution in the brain. The different types of adenylyl cyclase are activated by Gsa as well as the diterpene forskolin, but are differentially regulated by Gia, the Py subunits, Ca, and by phosphorylation. This provides for fine control of adenylyl cyclase enzyme activity and regulation by other effector pathways. 

The cascade of the second messenger system for histamine release in the ECL cell has not been characterized. Isolated ECL cells studied in a perfusion chamber exhibit a biphasic increase in intracellular calcium when exposed to gastrin or PACAP. An early transient, presumably due to the release of calcium from intracellular stores, is followed by a steady-state increment due to caldum entry. Blockade of caldum entry by La blocks histamine release. It is likely that the increase in cell calcium causes the activation of a variety of calcium-dependent signaling pathways, including protein kinase C. The C kinase activator, the phorbol ester tetradecanoyl-13-phorbol acetate (TPA) stimulates histamine release, supporting the proposal that this protein kinase is a component of the calcium-dependent histamine-stimulation pathway. Because forskolin (an intracellular stimulant of adenylate cyclase) is also a potent agonist of histamine release, a role for cAAAP in histamine secretion is likely. This proposal is supported by increased cAMP levels in forskolin-stimulated ECL cells. 

---