How do chemical messengers in the extracellular fluid bring about changes in cell function? Give an example of a chemical messenger for each mechanism noted.

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College Answer

Overall answers lacked structure and depth, to what is a very fundamental topic. This topic 
is generally covered within the opening chapters of most physiology texts. Common errors 
were not answering the question, writing lists rather than describing and explaining, and 
poor categorisation. Candidates were expected to mention and give example for 
mechanisms such as hormones binding to cytoplasmic or intra-nuclear receptors, binding to 
transmembrane receptors coupled to G proteins, cAMP, cGMP, tyrosine kinase, etc.

Discussion

Googling this question brings one to an online copy of Ganong (23rd ed.) where Table 3 from Chapter 2 has wording which spookily resembles the college question: 

table of cell signalling from Ganong 23rd ed

There's even examples. Sure, one could laizily copy and paste the whole table into the discussion section for this SAQ, as this author has done. An alternative would be to offer something which actually answers the question.

Chemical messengers in the extracellular fluid can affect cell function by:

  • Directly acting on cell surface receptors or intracellular receptors
  • Acting via secondary messenger systems (signal transduction)

Chemical cell signalling can be further subclassified:

  • Autocrine signalling: transmitter excreted into the extracellular fluid return to bind surface receptors of the same cell.
    (example: in lung adenocarcinoma cells IL-6 is an autocrine growth promoter)
  • Juxtacrine signalling: the signalling molecules are anchored in the cell membrane of one cell, and bind to receptors on the surface of immediately neighbouring cells (example: TGFα signalling in epidermal cells at the edges of wounds)
  • Synaptic signalling: transmitters are released at synaptic junctions from nerve cells and act across a narrow synaptic cleft on a postsynaptic cell.
    (example: serotonin, dopamine, acetylecholine)
  • Paracrine signalling: transmitters diffuse in the extracellular fluid to affect neighbouring cells that may be some distance away.
    (example: fibroblast growth factor (FGF) family involved in embryological limb development)
  • Endocrine signalling: transmitters reach distant cell targets via the circulating body fluids, mainly blood. 

Types of cell receptors for chemical messengers can be classified according to whether they are on the cell surface or intracellular:

  • Cell surface receptors
    • Cell surface molecules (eg. GPIa-IIa receptors on platelets)
    • Transmembrane nonenzymes (cytokines, interferon-γ)
    • Transmembrane proteins with active domains eg. receptor kinases (insulin)
    • Ligand-gated ion channels (acetylcholine)
    • Voltage-gated ion channels (electrical signalling
    • G-protein coupled receptors (dopamine, noradrenaline)
  • Intracellular receptors
    • Soluble intracellular enzymes (eg. the action of paracrine nitric oxide on guanylyl cyclase)
    • Nuclear receptors (eg. corticosteroid receptors)
    • Receptors on the surface of intracellular organelles (eg. IP3 receptors on the surface of the endoplasmic reticulum)
    • Intracrine peptide hormone receptors (eg. parathyroid hormone-related protein)

Secondary messenger molecules are most easily classified according to their chemical characteristics:

  • 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

References

Uings, I. J., and S. N. Farrow. "Cell receptors and cell signalling." Molecular Pathology 53.6 (2000): 295.

Bradshaw, Ralph A., and Edward A. Dennis. "Cell Signaling: Yesterday, Today, and Tomorrow." HandBook of Cell Signaling. Academic Press, 2010. 1-4.

Gao, Sizhi Paul, et al. "Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas." The Journal of clinical investigation 117.12 (2007): 3846-3856.

Owen, Markus R., Jonathan A. Sherratt, and Simon R. Myers. "How far can a juxtacrine signal travel?." Proceedings of the Royal Society of London. Series B: Biological Sciences266.1419 (1999): 579-585.