1. Cyclic AMP (cAMP) - Many signal transduction events involve the linked actions of a cell surface receptor, G protein, and adenylate cyclase. These events either stimulate or inhibit the synthesis of the second messenger, cAMP, inside the cell. Many intracellular processes are controlled, in turn, by the level of that second messenger. cAMP can affect transcription by binding to a protein called CREB (cAMP response element binding protein), and the resultant complex controls transcription of genes, including those encoding particular receptors.

2. Cyclic GMP (cGMP) - Nitric oxide stimulates the synthesis of cGMP (see here). Many cells contain a cGMP-stimulated protein kinase that, like the cAMP-activated enzyme, contains both catalytic and regulatory subunits.

3. Calcium - Calcium ion can be considered a second messenger. Many cells respond to extracellular stimuli by altering their intracellular calcium concentration, which in turn effects biochemical changes either by itself or through its interaction with calmodulin. Calcium levels themselves are controlled in large part by second messengers, including cAMP. Because cAMP regulates calcium influx, calcium ion may be more of a third messenger than a second messenger.

4. Phosphoinositide/Diacylglycerol - Cytosolic calcium ion levels also can be increased by release from intracellular calcium stores. Access to these intracellular stores is controlled by the phosphoinositide system. In the phosphoinositide system, hormonal stimulus activates a reaction that generates two second messengers. A specific lipid in the phosphoinositide family, phosphatidylinositol 4,5-bisphosphate (PIP2), is a membrane-associated storage form for two second messengers. As shown in Figure 23.14, steps in the process include the following:

a. An agonist binds to a receptor.

b. Receptor binding stimulates a G protein (see here) to bind GTP, just as occurs during the activation of adenylate cyclase.

c. The G protein activates phospholipase C, which in turn cleaves PIP2 to yield two products, namely sn-1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (InsP3) (see here). Both of these products act as second messengers. Therefore, the cleavage of PIP2 by phospholipase C is the functional equivalent of the synthesis of cAMP by adenylate cyclase.

d. Inositol trisphosphate stimulates the release of calcium from its intracellular stores in the endoplasmic reticulum . The release of calcium ion has various effects on intracellular metabolism, as noted earlier, but it also contributes to the second-messenger role of diacylglycerol.

e. Diacylglycerol stimulates membrane-bound protein kinase C. In order for it to be active, protein kinase C requires calcium ion (hence the "C" designation) and a phospholipid (specifically, phosphatidylserine). Diacylglycerol stimulates protein kinase C activity by greatly increasing the affinity of the enzyme for calcium ions. The requirement is specific for the sn-1,2-DAG; neither the 1,3- nor the 2,3-isomer is active.

f. Protein kinase C phosphorylates specific serine and threonine residues in target proteins. As with cAMP-stimulated protein kinase, the specific cellular responses to protein kinase C activation depend on the ensemble of target proteins that become phosphorylated in a given cell. Known target proteins include calmodulin, the insulin receptor, the -adrenergic receptor (see here), the glucose transporter, HMG-CoA reductase, cytochrome P450, and tyrosine hydroxylase.

After its release from PIP2, three sequential hydrolytic steps convert inositol trisphosphate back to inositol, which is then reincorporated into phosphatidylinositol, to regenerate PIP and PIP2. The last hydrolytic step, the hydrolysis of inositol monophosphate to inositol, is specifically inhibited by lithium ion. This blockage inhibits the resynthesis of InsP3 by depleting the cell of inositol. Given that the phosphoinositide messenger system is widely used in nervous tissue, the action of lithium ion may be related to its efficacy in the treatment of manic-depressive disorder.

Some of the processes controlled by the phosphoinositide system are listed in Table 23.5.

Phospholipases other than phospholipase C are also stimulated by G proteins. Arachidonic acid, released from phosphatidylcholine, is the major metabolic precursor to eicosanoids. Phospholipase A2, which releases fatty acids from glycerophospholipids, also interacts with G proteins, and phospholipase D (see here) is thought to participate in signal transduction via diacylglycerol formation. In addition, some phospholipases are controlled by Ca²⁺.

1. Neurochemistry and Second Messenger Functions

2. Second Messenger Cascades