Regulation of drug receptor number and activity

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... regulation of receptor number and activity". In general, it can be said that drug receptor numbers can be upregulated or downregulated by feedback loops designed to maintain some sort of homeostasis.  Receptor activity can also be modified by various stimuli, which might have constructive effects or which might be something pathological.

In the historical SAQs this topic has appeared only once, and even then only in a very peripheral sense. Question 15 from the second paper of 2014 explored the terms "tachyphylaxis" and "tolerance", which is broadly related to the regulation of receptor number and activity. Because the rest of the discussion of tolerance and tachyphylaxis belongs to the syllabus section on variability in drug response, these matters will only be discussed in a brief and superficial manner here.  

Probably the best reference for this topic has to be Chapter 43 from Anesthesiology Core Review (2014), by Vashishta and Berrigan. It is best because it is brief, no more than three printed pages. Simple lists of definitions from classic textbooks (eg. Stoelting, Peck & Hill) will also suffice. For an indepth overview, one may wish to read Littleton (2001). Most of this chapter was constructed on the basis of Littleton.

In summary:

• Receptor regulation  is the homeostatic increase or decrease in receptor activity or number, in response to activation or blockade.

Mechanisms of regulation and their examples include:

• Upregulation by synthesis
  • Acetylcholine receptor at the neuromuscular junction, upregulated by loss of acetylcholine following denervation
• Downregulation by endocytosis
  • SERT​​​​​​​​​​​​​​ reuptake protein endocytosis occurs in response to SSRIs
• Decreased activity by uncoupling of receptors from second messenger systems
  • ​​​​​​​​​​​​​​Opiate tolerance (initially) is mediated by dampening of secondary messenger signal transduction
• Decreased activity by depletion of a finite store of second messenger
  • ​​​​​​​​​​​​​​Tachyphylaxis
• Tolerance results from this: larger doses required to produce the same effect.
  • Tolerance can be divided into pharmacokinetic (clearance-related), pharmacodynamic (receptor-related), physiological (homeostatic adaptation to effect) and behavioural (learned compensation for the effect).
• Tachyphylaxis: a rapid decrease in response to repeated doses over a short time period 

Receptor regulation

Regulation of receptor proteins is a form of homeostatic control which takes place at the cellular level. Excesses of receptor stimulation can be harmful to cells, for instance in the example of "excitotoxicity" where the neurotransmitter glutamate acts as a neurotoxin.  An early simplistic model of this had suggested that the excess stimulation of a receptor would result in the production of a signal which suppresses the expression of the gene encoding that receptor. Similarly, decreased receptor stimulation results in the generation of additional receptor proteins and therefore development of increased sensitivity. In summary:

• Drugs (or endogenous ligands) binding to receptors produce a downstream effect
• In most circumstances, this downstream effect triggers regulatory mechanisms
• Regulatory mechanisms are designed to homeostatically respond to receptor activation, i.e. to dampen the response where it is exaggerated, or to amplify it where it is deficient.
• There are several mechanisms of such regulation:
  • Increase or decrease of the number of receptor molecules expressed on the cell surface (or wherever the drug finds its targets)
  • Increase or decrease of the concentration of downstream secondary messenger molecules (eg. cAMP)

This is an incomplete picture (Littleton, 2001) but for the purposes of answering a CICM Part I SAQ it will suffice. More detail will probably only serve to obscure the central messages one would wish to retain for those panicked ten minutes in the exam. Still, here it is.

Regulation of receptor number

This was the first hypothesis for how cells regulate their response to drugs. A receptor, it was theorised, must have some role in stimulating its own gene transcription when it is not bound by any ligand. As a result of this, the binding of an excessive amount of ligand will reduce the stimulus for receptor gene transcription, and fewer receptor molecules will be synthesised. In the course of normal wear and tear some of the old receptor molecules will degrade, and will not be replaced. As the result, the total number of receptors will diminish. Conversely, when the concentration of the ligand is reduced, there are many "free" unbound receptors, and they generate a powerful stimulus to produce more receptor molecules. In this fashion, excess agonist activity decreases receptor numbers, and excess antagonist activity increases it. 

What is the cellular mechanism for this? That remains to be established for the vast majority of receptors, and it is expected to be different for different receptor types and cell populations. The nature of the mechanism also has some implications for the rate at which upregulation and downregulation of receptor numbers occurs. For instance, if the downregulation of receptors involves merely turning off their transcription, then the effects will potentially take weeks to manifest (as old receptors will still be sitting on the cell surface for many days until they are degraded naturally). Alternatively, the downregulated surface receptors might get actively sucked up into the cell by endocytosis, tagged with ubiquitin and shredded in some lysosomal meatgrinder - a much faster process, probably taking hours instead of days. 

There are multiple examples of receptor number regulation, and the exam trainee probably only needs to have one or two for each mechanism. Zaliauskiene et al (2000) produce the example of the transferrin receptor, which - when downregulated- is lysosomally recycled quite rapidly, with a half-life of around 24 hours. Blakely et al (1998) discuss the SERT presynaptic serotonin transporters and agree that there are complex regulatory mechanisms involved which involve the phosphorylation of SERT proteins, tagging them for the endocytic pathway.  Another example is the population of acetylcholine-associated sodium channels at the neuromuscular junction, described by Martyn et al (1995). The loss of acetylcholine (eg. in denervation, such as stroke or spinal cord injury) produces a massive proliferation of these channels, making the use of suxamethonium unsafe.

Regulation of receptor function

Regulation of secondary messenger systems

Occasionally, the downregulation of a receptor is completely unrelated to the absolute number of receptors and is more related to their function. An example is opiates. It appears that the dominant mechanism of opiate receptor downregulation is a dampening of the secondary messenger systems. Harrison et al ( 1998) quote radiolabelled ligand binding studies which demonstrated that (at least initially) the number of opioid receptors remained the same even as the effect diminished. 

Alteration of substrate availability

Regulation of receptor function may be even further downstream. The number of receptors may be unaffected, and the secondary messenger system may remain unchanged, but the receptor function may be altered by repeated drug administration purely because that receptor mediates the molecular traffic of some finite substrate, which can become depleted by constant activation or by replacement with another substrate. Nils-Erik Andén demonstrated this with metaraminol in 1964.