Second messenger systems

This chapter is related to the aims of Section C(iv) from the 2023 CICM Primary Syllabus, which expects the exam candidate to "explain receptor activity with regard to... second messengers and G proteins". 

This has only appeared in the past papers once, but - given how few pharmacodynamics questions there are - that gives it a substantial percentage share of the total.  Question 2 (p.2) from the second paper of 2007 asked the candidates to "describe the term second messenger". An accurate answer would report that "second messenger" is a compound two-word term, one of the most common technical glossary item employed to give more precision than either word alone would have, not being exact synonyms.  However, judging from the college answer they expected the candidates to define the term instead. It is easy to miss these subtle differences.

For published literature on this subject, one cannot go past the (free, online) Chapter 20 from Molecular Cell Biology (Lodish, 2000). If one has institutional access or money, one may make use of Goodman and Gilman's Chapter 3 (which lists the systems but offers little in the way of definition). Once one gets to a certain point of sophistication, the definition for certain terms probably becomes assumed intuitive knowledge (eg. this article from Spindel, 2005)

A definition of a "second messenger"

The college definition from the answer to that one SAQ on this topic is somewhat lacking, insofar as it fails to define the term in a scientific-sounding way.

"... receptor binding is coupled to a subsequent series of intracellular biochemical events that precipitate the ultimate hormone/drug effect"

is what they came up with. The failure to generate a satisfactory definition is no fault of the examiners, as different definitions can be found in just about every medical dictionary.  A whole selection can be reproduced for comparison:

" intermediary molecule that is generated as a consequence of hormone receptor interaction"

"...a chemical substance inside a cell that carries information farther along the signal pathway from the internal part of a membrane-spanning receptor embedded in the cell membrane"

"...any of various intracellular chemical substances...that transmit and amplify the messages delivered by a first messenger to specific receptors on the cell surface"

To add to the growing list of unsatisfactory definitions would be negligently wasteful of the trainee's time, and therefore well in the spirit of this website. One could, therefore, describe a second messenger as an intermediate molecule for an intracellular signal transduction cascade, which is used to transmit and amplify the signal between an extracellular stimulus and an intracellular effector. These molecules were discovered in the late 1960s by Earl W. Sutherland's group, who received a Nobel Prize in Medicine for their experiments. The term was coined around that era, to discriminate the intracellular signal transduction pathway mediators from the "first messenger" hormones such as glucagon or adrenaline.

Characteristic features of a second messenger system

The basic characteristics of a second messenger system can be summarised for exam purposes as follows:

  • The drug-receptor or receptor-ligand interaction often does not result in the direct activation of the intracellular effector
  • Instead, often an intermediate molecule is used as a signal to the effector.
  • This intermediate molecule is synthesised or released in response to the receptor-ligand interaction, and then degraded afterwards. 
  • The rate of synthesis and degradation of this molecule is tightly regulated to control the magnitude of response to receptor activation, and this regulation can be used to amplify or dampen the response.
  • The second messenger molecule can act locally, or can diffuse distally to convey the signal to a multitude of targets; and multiple second messenger systems can interact to produce complex responses to receptor-ligand binding.

Examples of second messenger systems

It is possible to classify the second messenger systems into several broad types:

  • Hydrophobic molecules, such as DAG and phosphatidylinositols which do most of their work from the intermembrane space
  • Hydrophilic molecules such as  cAMP, cGMP and IP3 - which diffuse freely in the cytosol
  • Ions such as ionised calcium, potassium and sodium
  • Gases, such as nitric oxide (NO) and carbon monoxide (CO) which diffuse easily through lipid and water alike.
  • Soluble proteins such as Jak/STAT, NF-kB, etc

These are perhaps best dealt with in their own chapters. 


Lodish, Harvey. Molecular cell biology. Macmillan, 2008.

Bowness, J. M. "Epinephrine: cascade reactions and glycogenolytic effect." Science 152.3727 (1966): 1370-1371.

Sutherland, Earl W. "On the biological role of cyclic AMP." Jama 214.7 (1970): 1281-1288.

Worley, Paul F., Jay M. Baraban, and Solomon H. Snyder. "Beyond receptors: Multiple second‐messenger systems in brain." Annals of neurology 21.3 (1987): 217-229.

Gorelick, F. S. "Second messenger systems and adaptation." Gut 28.Suppl (1987): 79.

Spindel, Eliot R. "Second-messenger systems and signal transduction mechanisms." Endocrinology. Humana Press, 2005. 35-48.

Garattini, Silvio. "Pharmacology of second messengers: A critical appraisal." Drug metabolism reviews 24.2 (1992): 125-194.

Bowman, W. C. "Second messenger systems as sites of drug action." Proceedings of the Royal Society of Edinburgh, Section B: Biological Sciences 99.1-2 (1992): 1-17.