Receptors - A brief note

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What is a receptor?

Different people have different ideas about what a receptor is. I rather like the definition of Hucho:

Receptors are proteins interacting with extracellular physiological signals and converting them into intracellular effects

This definition is by no means perfect, but seems far more useful than the blurry definition you find in so many pharmacology textbooks, along the lines of 'a receptor is any functional macromolecular component of an organism to which a drug binds'. We should perhaps avoid semi-religious bickering about the 'essential nature' of receptors, and look at how well the definition works for us!

The most important concept is that the receptor:

  1. Receives a signal; and
  2. transduces the signal to
  3. an effector mechanism.

Types of Receptor

If we accept Hucho's definition, we can identify at least four groups of receptors:

Here are the major receptor groups in tabular form:

Types of receptor
 Receptor enzymes Ligand-gated ion channels G-protein-coupled receptors Transcription factors
Tyrosine phosphorylasesOther (Thr, Ser, guanyl cyclase)
Number of transmembrane domains 1 4 7 -n/a-
Examples insulin, EGF, PDGF, some lymphokines TGF beta(Ser Thr), atrial natriuretic peptide nicotinic cholinergic receptor, GABAA, Gln, Asp & Gly receptors Many receptors: most peptide hormones, eicosanoids, biogenic amines e.g. catecholamines Receptors for steroid hormones, thyroid hormone, vitamin D, retinoids.

Once we start looking at receptors in detail, and especially how they respond when we expose them to different ligands that bind to them, strange things start to happen! Exposing receptors to different molecules, singly or in combination, can give rise to a vast array of effector responses.

  1. Invariably, exposing the receptor to the endogenous ligand(s) normally found in the body gives rise to an agonist response - the normal 'positive' effect of the endogenous ligand is duplicated. In fact, we can often identify substances not normally found in the body which have either a more specific effect on a particular receptor than does the normal ligand, a greater affinity for a particular receptor, or even a greater biological effect (greater intrinsic activity).

  2. It is usually possible to identify specific antagonists that antagonise the effect of agonists. Such antagonism is commonly reversible by increasing the concentration of agonist (competitive antagonism) but sometimes we get lucky and find an antagonist that blocks the receptor by binding at a separate site, and this is not overcome by increasing the concentration of agonist. We call the latter non-competitive antagonism.

  3. A partial agonist is somewhere betwixt and between! In the absence of an agonist, the partial agonist may do a very good job of stimulating the receptor - however, if you add one of these to a preparation where the receptor is already exposed to a decent concentration of a full agonist, then the partial agonist will sit on the receptor and interfere, causing less agonist activity. As with an antagonist, this effect will be reversed by increasing the concentration of the agonist. We say that the effects of the full and partial agonist are subadditive.

  4. Even more peculiar is the inverse agonist. It's difficult (but not impossible) to explain how this works - if you take a preparation and add an agonist, you see a particular effect. Add an inverse agonist instead, and you see the opposite of the effect - for example benzodiazepines like diazepam cause sedation and drowsiness through their agonist effects at the GABAA receptor, while inverse agonists at this receptor cause hyper-excitability and even seizures!


Pharmacodynamics is the study of what happens at the receptor level, when the receptor and a 'ligand' for that receptor get down to business. Intimate knowledge of this interaction is the basis for rational drug design, understanding drug effects, and correct drug administration. It also allows us to understand disease states where receptor density or function is altered.

There are several theories about how, for example, agonists "bind to and activate" a receptor. Such theories have to explain the various effects of not only agonists, but also antagonists, partial agonists, and even inverse agonists. One such theory that seems to fit the facts rather well is as follows:

  1. The receptor exists in two forms ('conformations') which we can call 'active' and 'inactive'. The active receptor is normally in the minority, and gets the effector process cracking. The inactive receptor just sits there, biding its time.

  2. There is a dynamic equilibrium between the active and inactive forms of the receptor. Most of the receptors are inactive, but from time to time they flip over into the active state, this being counterbalanced by active receptors becoming inactive.

  3. Agonists shifts the equilibrium in the direction of the active form - by binding the active form more avidly, they drive things in the direction of activation.

  4. In contrast, competitive antagonists have equal affinity for both conformations, and all they do is get in the way of an agonist trying to bind to the active form. Similarly, partial agonists have only a slightly higher affinity for the active receptor than for the inactive form, so they display some agonism, but interfere with the function of a 'full' agonist.

  5. The attractive feature of this model is that it explains inverse agonists rather well. If there is a basal tendency of the receptor to be in the active state (as seems to pertain with GABAA receptors) then these active receptors will demonstrate a tonic, basal effect even in the total absence of agonist ligands binding to them! Add an inverse agonist with a preference for the inactive receptor, the equilibrium shifts to the left, and the tonic 'agonist' effect is reversed!

The above model is well-described in Goodman and Gilman.

Receptor Characteristics

Many proposals have been made as to how to identify a receptor. We now have molecular biological techniques for identifying putative receptors within the genome before we've even discovered the ligands (endogenous or otherwise) that stimulate these 'orphan receptors'. But we're still mainly concerned with the ligands, for it is mainly by characterising specific ligands that bind to a particular receptor, that we can use the effects of receptor stimulation to clinical advantage. Hucho again comes to the rescue, with the following criteria:

Note that if we accept a more fuzzy and broad definition of a receptor, then these criteria are difficult to apply!

Down and up- regulation

Receptor expression is usually dynamic - chronic stimulation of receptors often results in decreased numbers of receptors, while under- stimulation causes an increase in the number of receptors. There are many practical examples of this process, for example long term stimulation of beta-1 and beta-2 receptors causes their numbers to decrease (with profound effects on asthmatics and people in heart failure), while denervation of some structures may cause up-regulation and modification of receptors to a point where even mild stimuli cause substantial responses (for example in achalasia, and also in spinal cord injury).

Such changes are not necessarily just alterations in numbers of receptors - types and activities of receptors may also change. Over- or under-stimulation of one receptor can also have profound effects on other receptors (so called "heterologous desensitization").

Potency versus Efficacy

People who should know better are often impressed by the potency of a drug - somehow they feel that if drug A has the same effect as drug B at microgram concentrations, as opposed to milligram ones, that drug A is necessarily 'better' than drug B. This is of course silly - what we should be interested in is the maximum effect achieved by a drug, when we've saturated all the receptors with the drug. "How potent is the drug?" is the wrong question! The correct question is "Is the maximal effect of drug A greater than the maximal effect of drug B?" This question is closely allied to the definition of a 'full' agonist versus a partial one.

The term commonly used is efficacy - in other words, if two drugs occupy the same number of receptors on a tissue, and one drug elicits a greater biological response than the other drug (by its action on the receptor) then that drug has greater efficacy. {The term intrinsic activity is sometimes used to express more or less the same concept}.

A little maths

The Law of Mass Action assumes that the rate of an elementary reaction depends on the concentration of each individual 'species' involved in the reaction. For example in the formation of B from A:

A ==> B

the more A we have, the faster we form B. If we express this mathematically, we say:

-d[A]/dt = k[A]         [Equation 1]

In other words, the rate of consumption of A is proportional to the concentration of A.

Similarly, where we have two substances A and B combining to form a complex AB:

A + B ==> AB

the corresponding differential equation is:

-d[A]/dt = k[A][B]         [Equation 2]

In other words, the rate of consumption of A depends on both the concentration of A and the concentration of B.

Now let's consider the case where we have a ligand binding to a receptor to form a ligand-receptor complex. Assume we have equilibrium, so the rate of formation of LR is the same as the rate of dissociation of LR into L + R:

  k1 (forward)  
Ligand + Receptor <=======>Ligand-receptor complex
  k2 (backwards)  

We apply the law of mass action to the forward reaction, and from Equation 2 we find:

-d[L]/dt = k1[L][R]

but we also know that because we have equilibrium, this rate of consumption of L is equal to the rate of dissociation of LR into its components, given by Equation 1:

-d[LR]/dt = k2[LR]

so therefore, equating the two:

k1 [L] [R] = k2 [LR]

We can rearrange this to:

( [L] [R] ) / [LR] = k2/k1

We have a special name for the ratio k2/k1 - we call it KD, the dissociation constant. To get a feel for what KD means, consider the case where exactly half of the receptors are occupied by ligand. Then the other half of the receptors are not occupied, so [R] = [LR], and therefore [L] = KD. Another way of saying this is that "KD is the concentration of ligand that at equilibrium will cause half the receptors to be ligand-bound". It's clear from this that the more tiny the KD, the more receptors are occupied at a given concentration of ligand - that is, the higher the affinity of the receptors for the ligand.

Fractional occupancy

Pharmacologists often use the term fractional occupancy to describe the fraction of receptors occupied at a particular ligand concentration. It's obvious that the fractional occupancy is:

fractional occupancy = [LR] / [total receptor]

Which is another way of saying:

fractional occupancy = [LR] / ( [R] + [LR] )      [Equation 3]

We know from its definition that KD is given by:

KD = ( [L] [R] ) / [LR]

So if we rearrange to get an equation describing [LR] and then substitute this in Equation 3, we get:

fractional occupancy = [L] / ( KD + [L] )

Why are pharmacologists so interested in the fractional occupancy? Well, it makes sense that the effect of a drug should depend on the fraction of receptors that are actually occupied. So the measured effect should depend on the fractional occupancy, which in turn should depend on [L] / ( KD + [L] ). Also, if we have measured the maximum effect (where almost 100% of the receptors are occupied) and we know the fractional occupancy, then we can determine the effect for any given concentration of a ligand. This effect will be given by:

Effect = maximal effect * [L] / ( KD + [L] )

If you sit down and plot a graph of effect versus [L] you'll soon see that we get a simple rectangular hyperbola:

Graph of effect
plotted against concentration of ligand - a rectangular hyperbola

Use graphs to compare drugs

Pharmacologists are never happy with simplicity. No, that's unfair. There's a darn good reason why they often alter the above graph, plotting the log of the ligand concentration on the x axis, and this is because they often need to draw graphs that involve concentrations of ligand that vary by several orders of magnitude. If we draw the graph thus we get a sigmoid curve:

Graph of effect
plotted against LOG concentration of ligand - a sigmoid curve

The advantage is that we can now compare different ligands, and even examine the case where we add (for example) a partial agonist to a preparation containing a full agonist.

Let's first compare three drugs, A, B and C:

Graph of effect
of three different drugs

You can see that drug A is more potent than the other two, and that the maximal response for drug C is less than that for the other two - drug C is a partial agonist when compared with drug A or drug B.

Next, let's look at the effect on drug A of adding a competitive antagonist (X) and then a non-competitive antagonist (Y). See how increasing concentrations of drug A can overcome the effect of the competitive antagonist, but not that of the non-competitive one!

Graph of effect
of different antagonists


We've attempted to cover receptor basics, but there's lots more. Consult the following references for further information - for example, it's interesting to work out the KD of an antagonist using the Schild regression, and to understand how Saturation Radioligand Assays work!


  1. Ross EM. Pharmacodynamics in Hardman JG, Limbird LE et al. [ed] Goodman & Gilman's The pharmacological basis of therapeutics. 9ed. McGraw-Hill 1996. ISBN 007 0262667.

  2. Hucho F in. Hucho F [ed] Neurotransmitter Receptors. Elsevier 1993 pp 3-14 ISBN 0444 899030.

  3. There's a good web introduction to receptor kinetics here. Go visit it!

Last update: 17 November 1999 Web page author