Many water soluble hormones do not cross the cell membrane, but instead cause effects within the cell via a second messenger. 
 
 

There are several known second messenger systems
 
 

The first of these systems cAMP , was discovered by Sutherland and his colleagues in the 1950’s. Cyclic AMP is a small cyclized monophosphate and it is produced from ATP by the enzyme adenylate cyclase.
 
 

In a most often used example when glycogen acts on receptors in the liver, cyclic AMP is produced. The second messenger goes on to active a cascade of enzymes that allow the mobilization of glucose from glycogen.
 
 

Many different hormones working in many different cells utilize cyclic AMP.

In

Adipose tissue epinepherine increase in triglyceride hydrolysis

Cardiac muscle epinepherine increase contraction rate

Kidney vasopressin reabsorption of water

Bone cells parathyroid hormone reabsorption of calcium from bone
 
 

For a second messenger to work effectively it must have the following characteristics:

1. Amplification – when a few hormone molecules signal the cell, it needs to respond with a signal that is strong enough to get a job done without repeated high levels of stimulation.
2. Control --- eventually a response must be shut down, and there are instances when its necessary to respond a little or a lot – so control is needed.
3. Specificity – when a hormone is released, a given cell should respond in a specific way. Not all cells will respond to this hormone. The hormone may not have the same effect in all the cells that do respond.

We begin when a hormone, like epinepherine, binds to a receptor on a cell surface—say a smooth muscle cell. 

1. The hormone and receptor bind.
2. . The receptor binds to a complex of proteins – the G proteins
3. The alpha subunit of the G complex binds to GTP (rather than GDP) and is activiated.
4. Ga + GTP binding activates adenyl cyclase
5. Cyclic AMP is produced
6. Cyclic AMP binds to an inhibitory subunit of an enzyme, phosphorylase A
7. Phosphorylase A cleaves off inhibitory unit and is activated
8. Many enzymes in a cell are phosphorylated and activated by this enzyme

1. Hormone unbinds to receptor
2. GTP is converted to GDP in the G complex
3. Adenyl cyclase is inactivated
4. Cyclic AMP is converted to AMP by the action of the enzyme phosphodiesterase.

Example:

In the intestine, epinepherine stimulates fluid secretion. The intestinal cells of the crypts of Lieberkuhn secrete NaCl from the blood into the intestinal lumen. Cyclic AMP binds to the apical Cl channel and allows it to open – water is drawn osmotically across the cell into the lumen also and so water is excreted via the feces.
 
 

Cholera toxin increases this fluid loss. The binding of the toxin to the intestional cells causes a large increase in the level of cAMP in the cells by inhibiting the conversion of GTP bound to Ga to GDP. So adenyl cyclase is not turned off and diarrhea results.
 
 

This scenario then meets our first criterion – because it allows a rapid amplification of the effects of the hormone. 

Each receptor can affect a number of G proteins, and they in turn can activate a number of molecules of adenylate cyclase and they and produce thousands of molecules of cyclic AMP per second.
 
 

What about 2) the shut down and control phases of the activation ??
 
 

Well first, the same cell that is being stimulated by a hormone may also be stimulated by an antagonistic hormone. For example in the fat cell, glucagon, epinepherine, ACTH and vassopressin all cause a rise in cyclic AMP; but prostaglandin E1 and adenosine inhibit this increase. It appears that these agents bind to their own receptors and that these receptors activate another G complex that is inhibitory for adenylate cyclase. (when bound to GTP). A second down regulator is phosphodiestease – this enzyme is normally present and active in the cell and converts cyclic AMP to AMP, so it is always competing for cyclic AMP and prevents its accumulation. (Phosphodiesterase is inhibited by caffeine and theophylline.

That brings us to point three – specificity – here we can say that a cell must have specific proteins to be able to be affected by a given hormone. These proteins will include the receptors themselves – the type and amount and the proteins that can be phosphorylated by protein phosphorylase A.
 
 

Each receptor may work through a different second messenger or have different binding affinities. For instance, epinepherine may trigger a response in alpha receptors or beta receptors. A given cell may have both types. One of the general effects of alpha receptors is to mediate vasoconstriction of smooth muscle. Beta receptors increase heart rate and glucose mobilization. We also have subtypes of receptors; alpha 1 which acts through the IP3 messenger and alpha 2 which inhibits cAMP production. Beta 1 and B2 both increase cAMP . Beta 2 has the highest affinity for cAMP.
 
 

As you can imagine the challenge of pharmacology is to find agonists (+) and antagonists (-) for specific receptors. For instance, beta stimulation increases the heart rate and dialates the smooth muscle leading to the bronchii. If a beta blocker is used to slow the heart rate, it could have a very undesirable effect of cutting off oxygen. However B1 receptors primarily affect the heart and B2 receptors the constriction of the airways (propranolol – non-selective beta vs atenolol.