Describe the term second messenger.

Give an example of a drug that manifests its action via a second messenger.

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College Answer

Second messenger-Hormone/drug - receptor binding is coupled to a subsequent series of
intracellular biochemical events that precipitate the ultimate hormone/drug effect.
Examples are G proteins an energy dependent process by which there is hydrolysis of G
protein-associated GTP to GDP. There are both stimulating and inhibitory proteins
which subsequently act to increase or decrease activity of the enzyme adenylyl cyclase,
resulting in increased levels of cyclic adenosine 3 ',5'-monophosphate ( cAMP) in the cell
which in turn activates protein kinases that phosphorylate various proteins, ion channels, and second messenger enzymes. Also G proteins stimulate hydrolysis of phosphatidyl-inositol-4,5-bisphosphate (PIP2) generating inositol-1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG). Both systems increase intracellular calcium.

Discussion

The college answer leaves much to be desired.

According to one of the (many) definitions, a second messenger is

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

The basic characteristics of a second messenger system are 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.

A good all-purpose example is the β-1 adrenergic receptor. Wheeler (2005) gives a good overview, in case the need for one ever comes up

  • A ligand (eg. adrenaline) binds the extracellular domain of the receptor
  • The intracellular domain is coupled to a G-protein
  • The G-protein activates adenylyl cyclase
  • The activated cyclase enzyme catalyses the conversion of ATP into cyclic AMP (cAMP)
  • cAMP catalyses the activation of protein kinase A (PKA)
  • PKA then phosphorylates serine and threonine residues on specific protein substrates, which act as the end effectors of the β-1 adrenergic receptor activation, producing effects such as increased myocyte contractility and increased rate of depolarisation in excitable tissues
  • The concentration of cAMP is regulated by phosphodiesterases which degrade it, dampening the signal transduction. This regulatory system is itself susceptible to pharmacolgoical manipulation, for example by phosphodiesterase inhibitors such as milrinone.

References

References

Wheeler-Jones, Caroline PD. "Cell signalling in the cardiovascular system: an overview." Heart 91.10 (2005): 1366-1374.

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.