The structures of receptors are very diverse and include the following major categories, among others:
The structures and actions of receptors may be studied by using biophysical methods such as X-ray crystallography, NMR, circular dichroism, and dual polarisation interferometry. Computer simulations of the dynamic behavior of receptors have been used to gain understanding of their mechanisms of action.
Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action in the following equation, for a ligand L and receptor, R. The brackets around chemical species denote their concentrations.
One measure of how well a molecule fits a receptor is its binding affinity, which is inversely related to the dissociation constant Kd. A good fit corresponds with high affinity and low Kd. The final biological response (e.g. second messenger cascade, muscle-contraction), is only achieved after a significant number of receptors are activated.
Affinity is a measure of the tendency of a ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate its receptor.
Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist:
Note that the idea of receptor agonism and antagonism only refers to the interaction between receptors and ligands and not to their biological effects.
A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist. The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive activity of the cannabinoid receptor.
The GABAA receptor has constitutive activity and conducts some basal current in the absence of an agonist. This allows beta carboline to act as an inverse agonist and reduce the current below basal levels.
Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors).
The central dogma of receptor pharmacology is that a drug effect is directly proportional to the number of receptors that are occupied. Furthermore, a drug effect ceases as a drug-receptor complex dissociates.
Ariëns & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of ligands bound to receptors.
In contrast to the accepted Occupation Theory, Rate Theory proposes that the activation of receptors is directly proportional to the total number of encounters of a drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, not the number of receptors occupied:
As a drug approaches a receptor, the receptor alters the conformation of its binding site to produce drug—receptor complex.
In some receptor systems (e.g. acetylcholine at the neuromuscular junction in smooth muscle), agonists are able to elicit maximal response at very low levels of receptor occupancy (<1%). Thus, that system has spare receptors or a receptor reserve. This arrangement produces an economy of neurotransmitter production and release.
Cells can increase (upregulate) or decrease (downregulate) the number of receptors to a given hormone or neurotransmitter to alter their sensitivity to different molecule. This is a locally acting feedback mechanism.
The ligands for receptors are as diverse as their receptors. GPCRs (7TMs) are a particularly vast family, with at least 810 members. There are also LGICs for at least a dozen endogenous ligands, and many more receptors possible through different subunit compositions. Some common examples of ligands and receptors include:
Some example ionotropic (LGIC) and metabotropic (specifically, GPCRs) receptors are shown in the table below. The chief neurotransmitters are glutamate and GABA; other neurotransmitters are neuromodulatory. This list is by no means exhaustive.
|Endogenous Ligand||Ion channel receptor (LGIC)||G protein coupled receptor (GPCR)|
|Receptors||Ion current[nb 2]||Exogenous Ligand||Receptors||G protein||Exogenous Ligand|
AMPA, and Kainate receptors
|Na+, K+, Ca2+||Ketamine||Glutamate receptors: mGluRs||Gq or Gi/o||-|
|Cl− > HCO−3||Benzodiazepines||GABAB receptor||Gi/o||Baclofen|
|Acetylcholine||nAChR||Na+, K+, Ca2+||Nicotine||mAChR||Gq or Gi||Muscarine|
|Glycine||Glycine receptor (GlyR)||Cl− > HCO−3||Strychnine||-||-||-|
|Serotonin||5-HT3 receptor||Na+, K+||Cereulide||5-HT1-2 or 4-7||Gs, Gi/o or Gq||-|
|ATP||P2X receptors||Ca2+, Na+, Mg2+||BzATP||P2Y receptors||Gs, Gi/o or Gq||-|
|Dopamine||No ion channels||-||-||Dopamine receptor||Gs or Gi/o||-|
Enzyme linked receptors include receptor tyrosine kinases (RTK), serine/threonine-specific protein kinase, as in bone morphogenetic protein and guanylate cyclase, as in atrial natriuretic factor receptor. Of the RTKs, 20 classes have been identified, with 58 different RTKs as members. Some examples are shown below:
|RTK Class/Receptor Family||Member||Endogenous Ligand||Exogenous Ligand|
Receptors may be classed based on their mechanism or on their position in the cell. 4 examples of intracellular LGIC are shown below:
|cyclic nucleotide-gated ion channels||cGMP (vision), cAMP and cGTP (olfaction)||Na+, K+|
|Intracellular ATP receptors||ATP (closes channel)||K+|
Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the hormone is produced at decreased level; this gives rise to the "pseudo-hypo-" group of endocrine disorders, where there appears to be a decreased hormonal level while in fact it is the receptor that is not responding sufficiently to the hormone.
Nicotine ... is a natural alkaloid of the tobacco plant. Lobeline is a natural alkaloid of Indian tobacco. Both drugs are agonists are nicotinic cholinergic receptors ...