Interested in learning about individual receptors:
I've discussed about the following receptors in my other hubs:
- Cholinergic receptors
- Adrenergic receptors
- Histamine receptors
- Dopamine receptors
- 5 Hydroxytryptamine (Serotonin) receptors
- Opioid receptors
- GABA receptors
Also read about:
- Methods of studying receptors
- Number of receptors in a cell
- Receptor Regulation
- Life cycle of receptors
- G proteins
- Second messengers(cAMP, calcium, cGMP, IP3, DAG and calmodulin)
Welcome to ePharmacology! Today we will discuss how a drug acts.
Nowadays it has been possible to understand the mechanism of action of many drugs.
Some drugs act by interacting with their specific receptors.
Some drugs produce their effects by modifying the ion channels.
There are a number of drugs that produce their response by interacting with enzymes or carrier proteins.
In addition, some drugs act simply by physical or chemical reaction.
Let's discuss about receptors!
Did you know?
Ligands are neurotransmitters, hormones, autocoides, and a large number of drugs. These substances are also called first messengers.
What is a Receptor?
Receptor is the component of the cell to which a ligand (a molecule that binds to another molecule) specifically binds and may produce responses. For example, acetylcholine specifically binds with cholinergic receptor but not with histamine receptor. Some drugs also bind with plasma proteins or erythrocytes. But these binding are nonspecific and are not related with the receptor.
The concept of receptor was originally coined independently by the experimental work of P Ehrlich (a German physician, biologist, chemist) and J. N. Langley (an English physiologist) in latter part of nineteenth and early part of twentieth centuries. Their experiments showed that nicotine, an alkaloid obtained from tobacco, caused contraction of skeletal muscle. South American arrow poison curare inhibited nicotine-induced contraction of skeletal muscle. But the response of that muscle to direct electrical stimulation was not blocked. The response to nicotine persisted even after denervation of the muscle. From this initial experiment. they concluded that nicotine and curare acted on the same component of the cell.
Subsequently, it had been possible to identify a number of receptors and their specific agonist and antagonists. Isolation of receptors with their subunits and determination of modular weight have greatly enriched this field.
Receptors in 5 minutes
Where are receptors located?
Most of the receptors are located at the plasma membrane (what is the plasma membrane?). But receptors for steroid hormones, thyroid hormones, or vitamin D are located within the cell. At the synapse, receptors are located both on presynaptic and postsynaptic sites. Presynaptic receptors are called autoreceptors. The function of autoreceptors are to regulate the synthesis and release of neurotransmitters, α2-adrenergic receptors, M2 receptors, and H3 receptors are the examples of autoreceptors.
After identification of opioid receptors to which morphine and related drugs act, the investigators tried to find out the endogenous substances that usually acted on those receptors. Subsequently, in 1975, the existence of endogenous peptides such as met-enkephalin, leu-enkcphalin, dynorphin had been established that acted on opioid receptors.
The term orphan receptor has been applied for which no functional ligand is identified.
What happens if receptors don't function normally?
A number of diseases develop due to abnormality in receptors. For example, an autoimmune attack on nicotinic cholinergic receptor causes myesthenia gravis. Inherited mutation of ACTH receptor leads to the development of resistance to ACTH.
What are the different types of Receptors? Classification of Receptors:
Receptors can be classified into four types on the basis of mechanism of action.
(Click to go to specific section)
- Ion-channel coupled receptors
- G protein-coupled receptors
- Tyrosine kinase related receptors
- DNA-linked receptors
Ion channel linked receptor
Ion channel-coupled receptors
There are a number of receptors (e.g. nicotinic cholinergic receptor, GABAA receptor, glycine receptor, 5-HT3 receptor, and P2x receptor) which act by opening the ion channels. This type of receptors are present at the outer surface of the plasma membrane.
Did you know?
α-Bungarotoxin is a peptide, having molecular weight of 7,800, obtained from the snake venom. It has high affinity for the nicotinic cholinergic receptor with slow rate of dissociation. Radio-labeled α-Bungarotoxin is used as a marker during solubilization and purification of the receptor.
Patients suffering from myasthenia gravis have impaired neuromuscular transmission primarily by noncompetitive mechanisms. In congenital myasthenia gravis, neuromuscular transmission can be impaired by mutations which alter the function of nicotinic cholinergic receptor.
Among these receptors, the molecular structure of nicotinic cholinergic receptor has been extensively studied. It is due to availability of source of receptors in high density and abundance (electric organs of the fish Torpedo and Electrophorus) and highly selective markers (e.g. α-bungarotoxin, cobra α-toxin) for the receptor.
The number of nicotinic cholinergic receptors in Torpedo electric organ is 1000 times more than that present in skeletal muscle. Nicotinic cholinergic receptor in skeletal muscle is a pentamer of four distinct subunits: α2βγδ. It has a molecular weight of about 280 kDa. The subunits are arranged around a funnel shaped central cavity, with the largest portion of the receptor being exposed towards the extracellular space. The central cavity is believed to be the ion channel, to a diameter of about 6.5 Å. The open channel is selective for cations. But carboxy terminus (C) and long amino terminus (N) are located extracellularly. The amino termini of the two α-subunits are believed to contain the acetylcholine-binding site.
G protein receptors
G protein-coupled receptors
Binding to this type of receptor leads to involvement of G proteins.
The G protein-coupled receptors include:
- Muscarinic cholinergic receptor
- Adrenergic receptor (α and β)
- Dopamine receptor
- 5-HT receptor
- Opioid receptor
- and receptors for many peptides.
Among these receptors, β-adrenergic receptor has been first fully characterized. β-Adrenergic receptor possesses seven transmembrane α-helices with both the extracellular amino terminus and the intracellular carboxy terminus vary greatly in length. Another highly variable region is the long third cytoplasmic loop that couples to the G protein. Deletion or modification of this section causes the receptor to bind with the agonist but can not associate with G protein. The ligand-binding domain appears to be present within the membrane on one or more of the α-helical segments, but not on the extracellular amino-terminus.
Tyrosine kinase receptors
Tyrosine kinase-linked membrane receptors
Tyrorine kinase-linked membrane receptors are:
- Insulin receptors
- Insulinlike growth factor 1 receptors
- Epidermal growth factor receptors
- Platelet-derived growth factor receptors
These receptors produce their responses both rapidly (i.e. metabolic response within a few minutes) or and slowly (i.e. regulation of DNA synthesis after many hours).
Tyrorine kinase-linked receptors are present at the plasma membrane and have two functional domains: an extracellular ligand binding domain, which is enriched in cysteine residues, and a cytoplasmic domain, which possesses the tyrosine kinase activity as well as the sites of autophosphorylation.
The extracellular part of insulin or insulin like growth factor 1 receptor contains two dissimilar chains (α and β) while the epidermal growth factor contains a single polypeptide. The tyrosine kinase domain of these receptors is similar.
Intracellular DNA linked receptors
DNA-linked receptors are intracellular receptors and are soluble proteins. Retinoic acid, corticosteroids, thyroid hormone, and vitamin D act by binding with these type of receptors.
These receptors are composed of ligand binding domain and a DNA-binding domain in its middle part. The structure of the DNA-binding domain involves coordination of a zinc atom by four cysteine residues which together form a structure called a zinc finger.
The fingers are believed to wrap around the DNA helix. Agonist first enters the cell and binds with a cytoplasmic receptor, which is normally associated with two molecules of 90 kDa heat shock protein (HSP90). The agonist displaces HSP90 and the agonist-receptor complex then translocates to the nucleus. Within the nucleus, the agonist-receptor complex can recognize specific base sequences and activates specific genes.
Receptors made simple
That's all for today!
In the next article we will discuss about individual receptors in more detail. So keep coming back to ePharmacology!
If you have any suggestions or if you want me to write about any topic then please feel free to send me a request!
Don't forget to comment on this article below!
© 2015 Oyon B