Cyclic AMP (cAMP)

This chapter is related to the aims of Section C(iv) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "explain receptor activity with regard to... second messengers and G proteins". Because such talk ultimately leads to the discussion of specific second messenger systems, a chapter on cyclic AMP appeared inevitable, because it is the final common pathway for many of the body's receptor signalling systems, and a popular drug target. Having said that, it certainly has never been the subject of a CICM exam question. As such, this entire subject area can be abandoned in favour of more fruitful revision topics;  a Part One candidate may successfully negotiate the exam and then go on to have a rich fulfilling career in Intensive Care Medicine with only a very foggy and dream-like appreciation of cAMP and its functions. Thus, most reasonable people would agree that the contents of this grey box will be enough:

• Cyclic adenosine monophosphate is a cyclic nucleotide secondary messenger
• It is produced when G-protein activates adenylyl cyclase
• It is degraded by phosphodiesterases
• Its main downstream targets include Protein Kinase A (PKA), EPAC and cyclic nucleotide-gated ion channels
• It plays an important role in mediating the response to catecholamines, glycogenolysis, insulin secretion, vision and olfactory sense.

If for whatever reason the candidate continues reading, it would be worth knowing that without resorting to piracy the best single article on this topic is The Cyclic AMP Pathway by Paolo Sassone-Corsi (2012). Another good resource is probably the original article by Sutherland et al (1968), who ended up being awarded the Nobel Prize in Medicine for the discovery of this second messenger system (it was the first second messenger system to be discovered). Though most will not require this, those few who are still tormented by a lack of detail may find their way to Bradshaw and Dennis' Handbook of Cellular Signalling (2009), where on page 1387 Kuszak & Sunahara's chapter (Ch.171, Adenylyl cyclases) exists to fill whatever terrifying psychological hole they might have.

Characteristics of cAMP and its place in biology

cAMP is a cyclic nucleotide. Nucleotides are composed of three main components:

• a phosphate group (or two, or three),
• a sugar (classically a pentose sugar such as ribose), and
• a nitrogenous nucleobase (in the case of cAMP, adenine).

The "cyclicness" is conveyed upon straight AMP by the bonds created between the phosphate group and the hydroxyl groups on the sugar, creating a little ring. 

This molecule is relatively short-lived. As a second messenger, it is a substance which by its very presence causes various chains of events to take place; as such its concentration is very precisely regulated. Its synthesis by adenylyl cyclases and its catabolism by phosphodiesterases is in a constant equilibrium. When one tries to measure the rate of cAMP turnover, one usually finds its intracellular lifespan is measured in minutes or seconds. For instance, in cultured fibroblasts under conditions of low stimulus the half-life of cAMP is about 1.4 minutes  (Barber & Butcher, 1980). 

Synthesis of cyclic AMP

cAMP is generated out of ATP by adenylyl cyclase. It is a transmembrane protein modulated by G-protein coupled receptors (i.e. they can increase or decrease its activity). It is activated by Gs proteins, and deactivated by Gi proteins.

Adenylyl cyclase converts ATP to cyclic AMP. The cAMP then activates downstream effector enzymes, of which the dominant species is  Protein Kinase A. PKA phosphorylates numerous effector enzymes and inhibits itself by phosphorylating phosphodiesterase, which converts cAMP back into "straight" AMP. This negative feedback loop is the target of various drugs, the activity of which is made more selective by the fact that there are multiple species of phosphodiesterase. For instance, PDE 1, 2, 3, 10 and 11 hydrolyse both cAMP and cGMP, whereas PDE 5 6 and 9 specifically hydrolyse cGMP only. Thus by targeting only PDE 5, sildenafil only inhibits the degradation of cGMP.

Effects of cAMP

Its effectors are:

• PKA (which phosphorylates numerous metabolic enzymes)
• EPAC (a guanine-nucleotide-exchange factor) which is involved in all sorts of things like cell adhesion, exocytosis, apoptosis, and gene expression
• cyclic-nucleotide-gated ion channels (usually these are unselective cation channels; one example is present in human rod and cone cells)

The observable effects include:

• mobilization of stored energy eg. β-adrenergic lipolysis / glycogenolysis
• vasopressin-mediated water retention
• parathyroid-hormone mediated calcium homeostasis
• response to catecholamines (β-adrenergic)

Though most of its work is intracellular, cAMP does make its way into the plasma and its concentration there is normally in the order of 15-30 nmol/L (Chasiotis et al, 1983). This concentration increases with exercise. People have even infused it into the bloodstream, demonstrating that it has some stimulant haemodynamic effects (Winer et al, 1971) - for instance, stimulating renin secretion and acting as a weak inotrope and vasodilator. The inodilator effects of cAMP derivatives such as dibutyryl-cAMP have been demonstrated (Taneyama et al, 1989), but clinical use of these milrinone-like drugs  was derailed by the appearance of actual milrinone.