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Individual Receptors: Cholinergic receptor, Adrenergic receptor, Histamine receptor & Dopamine receptor - ePharmacology

Updated on September 29, 2015
D = Drug, R = Receptor, DR = Drug-Receptor complex
D = Drug, R = Receptor, DR = Drug-Receptor complex | Source

In this hub on ePharmacology we will discuss about individual receptors in details! But before we start we should review about out general knowledge of receptors.

Nowadays it is apparent that heterogeneity of individual receptor occurs almost without exception. The existence of subtypes of different receptors is revealed by pharmacological study as well as molecular cloning of receptors. In the pharmacological study the subtypes of receptors are done using their specific antagonists. For example, acetylcholine causes contraction of both skeletal and smooth muscle. This acetylcholine-induced contraction of skeletal muscle is blocked by (+)-tubocurarine whereas atropine has no effect. On the other hand, acetylcho­line-induced contraction of smooth muscle is blocked by atropine, not by (+)-tubocurarine.

Rapid advances in the cloning of complementary DNAs that encode various receptors also helped in the subtyping of receptors.

Now we will discuss about the following receptors in length:

  1. Cholinergic receptors
  2. Adrenergic receptors
  3. Histamine receptors
  4. Dopamine receptors

Cholinergic receptors

Parasympathomimetic effects of the body is mediated by the action of released acetylcholine on cholinergic receptors.

Cholinergic receptors are of two types:

  1. Muscarinic cholinergic receptor
  2. Nico­tinic cholinergic receptor

In the nineteenth century, the compound muscarine was isolated from the psychoactive mushroom Amanita muscaria.
In the nineteenth century, the compound muscarine was isolated from the psychoactive mushroom Amanita muscaria. | Source

Subtypes of cholinergic receptors were named after the alkaloids originally used in their identification.

For example, the word musca­rine was derived from the poisonous mushroom and nicotine from the tobacco.

Nicotine - an alkaloid found in tobacco.
Nicotine - an alkaloid found in tobacco. | Source
Acetylcholine works on both muscarinic and nicotinic receptors
Acetylcholine works on both muscarinic and nicotinic receptors | Source

Acetylcholine has an unique property to bind with both muscarinic and nicotinic cholinergic receptors.

In case of bovine adrenal chromaffin cells, the plasma membrane contains both type of cholinergic receptors. It is the concentration of acetylcholine that will select which type of cholinergic receptors will be stimu­lated.

Using isolated adrenal chromaffin cells, it has been observed that acetyl­choline stimulates the muscarinic cholinergic receptors at concentrations less than 1 μM (μM = micromolar). At this concentration of acetylcholine, nicotinic cholinergic receptors are not stimulated. But nicotinic cholinergic receptors are stimulated when the con­centration of acetylcholine is more than 1 μM.

Muscarinic cholinergic receptors

Muscarinic receptors are G protein-coupled receptors. Pirenzepine, a muscarinic cholinergic receptor antagonist, blocks gastric acid secretion at concentration that does not affect several other responses to muscarinic agonist.

On the basis of this unique observation, muscarinic cholinoceptors can be further subdivided into three types: M1 M2 and M3. Ther are also two other types: M4 and M5.

Different sub-types of muscarinic receptors and their locations
Different sub-types of muscarinic receptors and their locations | Source

M1 receptors

M1 receptors are present in neurons and gastric parietal cells. The selective agonist is McN-A-343. Activation of this receptor causes increased PI turnover leading to increased formation of IP3 and diacylglycerol. Thus there is increased formation of intracellular free calcium concentration. The response of muscarinic agonist on this receptor can be blocked by both pirenzepine and atropine.

M2 receptors

M2 receptors are present in the cardiac and smooth muscle. The response of muscarinic agonist on the receptor is blocked by atropine. Activation of this type of receptor causes inhibition of adenylyl cyclase leading to reduced intracellular cAMP.

M3 receptors

M3 receptors are present in exocrine gland, smooth muscle and vascular endothelium. It acts by the same mechanism as M1 receptor.

M4 and M5 receptors

DNA cloning of muscarinic receptor leads to identification of two more receptors- M4 and M5. Their antagonists have not yet been identified.

Nicotinic cholinergic receptors

Nicotinic cholinergic receptors are present in skeletal muscle and ganglia are different. They are two types: N1 or NM and N2 NN.

NM receptors are present in skeletal muscle whereas NN receptors are present in neurons.

Sub-types of nicotinic receptors and their locations
Sub-types of nicotinic receptors and their locations | Source

Acetylcholine, nicotine, carbachol, and dimethyl-4-phenylpiperazinium (DMPP) are the agonists for nicotinic cholinergic receptor. Tubocurarine and gallamine are the antagonists for NM receptors. Hexamethonium (C6) is the an­tagonist for NN receptors. When acetylcholine acts on postsynaptic nicotinic cho­linergic receptor, there is transient increase in permeability to sodium and potassium ions. This results in a net inward current carried mainly by sodium ions, which depolarizes the cell and generates action potential. Subsequently there is an increased influx of calcium leading to increased intracellular free calcium concentration.

Ganglionic transmission in many cases is thought to be mediated by acetylcholine receptors containing an α3 subunit in combination with β4, α5. and sometimes β2 subunits. Some acetylcholine receptors containing α2, α3, α6, and α5 subunits are also found in brain.

Adrenergic receptors

Adrenergic receptors are of two broad subtypes- α and β.

α-adrenergic receptors are further subdivided into:

  • α11A and αIB) adrenergic receptors
  • α22A and a2B) adrenergic receptors

β-adrenergic receptors are further subdivided into:

  • β1 adrenergic receptors
  • β2 adrenergic receptors
  • β3 adrenergic receptors

Sub-types of adrenergic receptors and their locations
Sub-types of adrenergic receptors and their locations | Source

Phenylephrine is the α1-adrenergic receptor agonist and prazosin is the α1-adrenergic receptor antagonist. Clonidine and yo­himbine are the α2-adrenergic receptor agonist and antagonist respectively.

β1-adrenergic receptors are present in the cardiac muscle whereas β2-adrenergic receptors are found in smooth muscle and most other sites. β3-adrenergic receptors are present in the adipose tissue. Dobutamine is the selective agonist of β1-adrenergic receptors whereas practolol, metoprolol are the antagonists for β1-adrenergic receptors. Salbutamol and butoxamine are the agonist and antagonist of β2-adrenergic receptors respectively.

Histamine receptors

Histamine receptors are of ourf types:

  1. H1 receptors
  2. H2 receptors
  3. H3 receptors
  4. H4 receptors

Histamine receptor: subtypes, locations and mechanism of action
Histamine receptor: subtypes, locations and mechanism of action | Source

H1 receptors

Bronchial smooth muscles contain H1-receptor. Stimulation of this type of receptor causes contraction of the bronchial smooth muscles. The specific agonists for H1-receptor are 2-thiazolylethylamine and 2-methylhistamine. Activation of H1-receptor leads to increased formation of IP3 and diacylglycerol. Thus intracellular calcium concentration will be increased. H1-receptor antagonists are mepyramine, diphenhydramine, and promethazine.

H2 receptors

H2-receptors are present on the parietal cells of the stomach. Activation of this receptor increases the secretion of acid from parietal cells. Dimaprit and 4-methylhistamine are the selective agonists for H2-receptors. Activation of H2-receptors causes increase in intracellular cAMP level by stimulating adenylate cyclase. H2-receptors antagonists are cimetidine, ranitidine, famotidine, and nizatidine.

H3 receptors

H3-receptors appear to exist only in the CNS. At the histaminergic neuron H3-receptor may regulate the synthesis and release of histamine. This H3-receptor would be analogous to other autoreceptors (such as α2-adrenoceptor) that is involved in feedback regulation of neurotransmitter release. H3-receptor agonist and antagonist are α-methylhistamine and thioperamide respectively. Impromidine is the most potent H2-receptor agonist but is also a very potent antagonist of H3-receptor.

H4 receptors

H4-receptors are involved in changing the shape of eosinophil cells and in the chemotaxis of mast cells. They are currently under research.

Dopamine Receptors

There are at least five dopamine receptors (D1-D5) and these may be further divided into two subfamilies whose properties resemble the original D1 and D2 receptors defined biochemically.

The two subfamilies are often termed D1-like (D1, D5) and D2-like (D2, D3, D4).

Types of Dopamine receptors with their mechanism of action and locations
Types of Dopamine receptors with their mechanism of action and locations | Source

D1 receptor is present in the striatum and nucleus accumbens. D2 receptor is present in the pituitary mammotrophs. D1 receptor is associated with the stimulation of adenylate cyclase activity. Activa­tion of D2 receptor causes inhibition of adenylate cyclase. The D1 receptor is about 15-fold more sensitive to dopamine than D2 receptor. SKF 38393 is an example of a D1 receptor agonist and SCH 23390 is a D1 receptor antagonist. Apomorphine is the D2 receptor agonist. Butyrophenone, pimozide and sulpiride are the D2 receptor antagonists.

Analysis of the amino acid sequences of the dopamine receptor subtypes has shown that significant homologies exist, with the greatest homologies being found between members of the two subfamilies. Each receptor has been shown to contain seven stretches of amino acids that are hydrophobic and long enough to span the membrane. It seems, therefore, that each of the dopamine receptor conforms to the general structural model for a G-protein coupled receptor with an extracellular amino terminus and seven putative membrane spanning α-helices linked by intracellular and extracellular protein loops. One or more potential sites for glycosylation are found on the amino terminus and second extracellular loop. The helices are bundled together in the membrane to form the ligand binding site and there is an intracellular carboxyl terminus probably bearing a palmitoyl resi­due which may form a further link to the membrane.

The D1-like receptors have short third intracellular loops and long carboxyl termi­nal tails whereas the D2-like receptors have long third intracellular loops and short carboxyl terminal tails. This provides a structural basis for the division of the receptors into two subfamilies but is also likely to have a functional significance possibly related to the specificity of receptor/G-protein interaction.

Indeed the third intracellular loop of these receptors is thought to be important for the interaction of the receptor and G-protein, and for the D2-like receptors variants of these subtypes exist based on this loop. For example, there are short and long variants of the D2 and D3 receptors with the long forms having an insertion (29 amino acids for D2 long) in this loop. For the D4 receptor there are polymorphic variants in the human population with different length insertions in this loop.

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