Cell signalling and signal transduction systems

This chapter is vaguely relevant to Section E(iii) of the 2017 CICM Primary Syllabus, which expect the exam candidate to "outline the role of cellular receptors and the function of secondary messengers". It may, therefore, on the surface appear to be a direct recapitulation of the chapter on mechanisms of drug-receptor interactions and the entire secondary messenger system section from the Pharmacodynamics section, except for the following facts:

• Cells interact and signal each other in ways which are unrelated to drug action.
• Not all cell signalling receptors are drug targets.
• Not all drug targets are involved in cell signalling.

As such, it was worth including this chapter in the Cell Physiology section, notwithstanding the fact that Question 23 from the first paper of 2013 specifically asked about this subject. As the college did not release the SAQ marks for this paper, it is impossible to say how the candidates performed in answering this specific question, but one can surely share a feeling of profound disappointment from the total written pass rate (30%) and the examiner's lamentations. "Answers lacked structure and depth", they complained, considering especially that the subject "is a very fundamental topic... covered within the opening chapters of most physiology texts". The aim of this chapter is therefore to generate a memorable structure, and hang from it what content could be feasibly written in ten minutes so to at least generate the impression of depth.

Which "opening chapters" should you read from "most physiology texts"? Of the official textbooks, Ganong's Review of Medical Physiology has the best summary in Chapter 2 (it gets good around page 50 of the 23^rd edition), whereas the others really devote only a minimal attention to the subject. If one wishes to see what full attention to the subject might look like, one may look under the cover of the HandBook of Cell Signaling - the book itself covers all possible areas of this topic over 3 volumes and around 2300 pages. It doesn't actually contain any summary chapter of any sort, which might act as a reasonable compromise between reading the entire textbook or nothing at all; the reader is catapulted straight into chapters with titles like "Free Energy Landscapes in Protein–Protein Interactions". 

Classification of cell signalling

• Chemical:  signalling by the release of soluble transmitter molecules into the extracellular fluid. 
• Electrical: signalling by conducting an electrical current between connected cells
• Mechanical: signalling by affecting mechanical stretch receptors on the cell surface which are anchored to the cytoskeleton

Classification of chemical cell signalling

• 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

• 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

• 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