Understanding Receptors in Pharmacology

The cells in the body of any multicellular organism are always interacting with cells and systems of the body. There are multiple systems by which these cells communicate and the most common system uses is the receptor-ligand system.

There are multiple types of receptors:

G Protein receptors

Ligand-gated ion channel receptors,

tyrosine kinase receptors,

and nuclear receptors.

types of receptors.jpg

G protein-coupled receptors

Majority of all receptors will be G Protein receptors and these are found only in eukaryotic cells.

The receptor has the spans the entire bilayer of the membrane. The extracellular domain will bind to the ligand while the intracellular domain will transmit the signal to the inside of the cells.

The receptor has 7 transmembrane alpha helix structures. The agonist will come bind to this structure and activate the G Protein subunits this will cause the activation of an enzyme that or some other system that will activate the signal transduction.

The g Protein subunits consist of alpha, beta and gamma subunits. The alpha subunit will do most of the work and when inactive will remain ready and bout to the receptor.

U4.cp2.1_nature01307-f1.2

When the agonist attaches to the receptor the subunits are activated, GDP is converted to GTP allowing Alpha subunit to dissociate from the beta and gamma subunit (which remain together) and the receptor.

The G protein alpha subunit will then head to the effector to cause further signal transduction.

At this point, the GTP will be hydrolysed by the intrinsic hydrolysis activity of the system and will be ready for another round of activation.

500px-GPCR_cycle

The signal may be for activation or inhibition accordingly referred to as GS or Gi, respectively.

Now there are two primary pathways that textbooks explain for the signal transmission of G protein-linked receptors: cyclic AMP pathway and phosphatidylinositol signal pathway.

FIRST IMAGE OF GPROTEIN

In case of cyclic AMP pathway, the alpha subunit will activate the adenylyl cyclase enzyme to upregulate the synthesis of Camp which is now called the secondary messenger, the first begin the ligand that activated the G Protein signal transduction pathway.

After which the cAMP will be degraded. cAMP is an allosteric activator of PKC and so is normally expected to activate the same.

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Phosphatidylinositol signal pathway is also similar here the alpha subunit will cause activating of PHOSPHOLIPASE C. This causes phosphatidylinositol 4,5-bisphosphate (PIP2)  to be converted into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).

Thus here there are 2 secondary messengers and here DAG will activate the PKC. Whereas the IP3 will cause mitochondrial calcium channels to open.

IP3 DAG PATHWAY

 

Cardiomyocyte-G-protein-coupled-receptor-regulation-of-hypertrophy-The-catecholamines

The above image provides an advanced understanding of the role of receptors in pathology, in this case, heart failure via adrenergic stimulation.

Ligand-gated ion channels

These are probably the easiest to understand. They consist of a simple ion channel and a ligand binding site. GABA receptor is the best example and understanding it helps to understand the mechanism of action of benzodiazepines and barbiturates.

The ion channel usually houses the receptor binding site, in the case of GABA receptor, it’s a chloride channel. The ligand binds to the receptor opening the channel and causing the flow of the ion.

The below image shows the variety of locations for binding of different compounds on a single GABA receptor, the entire structure is seen in fact a chloride channel and the different locations on the channel act as receptor binding sites.

gaba_71.png

Tyrosine Kinase Receptors

Commonly quoted as JAK/STAT in textbooks as an example

These are important receptors that govern a lot of important functions. Insulin receptors are of this kind.

These receptors consist of the receptor itself and an intracellular tyrosine kinase domain, better understood with a reference image for study.

The basic concept is that a ligand binds to two such receptors for a signal to be transmitted the receptors “dimerise” and the tyrosine residues will phosphorylate each other this then allows for a signal transmission. There many kinds of these receptors and thus signal is then transmitted in a variety of manner. Activation of MAP kinase pathway occurs by this source.

tyrosine

 

 

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