What makes a drug work? Understanding “Receptors” (II)

Illustrations and quotations from this post are referenced from Basic & Clinical Pharmacology*.

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After some math from our previous post, in this post, we will cover the 6 common receptor types.

Intracellular receptors (for lipid-soluble ligands)

Figure 1 (Testbook: Figure 2–5)

The first type of receptor resides in the cell and regulates the gene expression on DNA. Therefore, the lipid-soluble ligands have to penetrate through the lipid-bilayer membrane and to bind to the receptors. Ligands working in this way include glucocorticoids and thyroid hormone.

Notably, as this receptor interacts with DNA expression, the produced protein will take some time to be generated and degraded. Therefore, the effect of such ligand may take a few hours and days to show (the time required for such gene to make a certain protein), and the effect of the ligand may take even longer time to be diminished (the turnover rate of the protein).

Ligand-regulated transmembrane enzymes

Allosteric activities

Figure 2 (Testbook: Figure 2–5)

This type of receptor locates in the cell membrane and has one extracellular binding site for the ligand. Subsequently after the ligand is bound, the resulting effect takes place in an allosteric and intracellular spot.

Ligand-regulated transmembrane enzymes with tyrosine kinase

Figure 3 (Testbook: Figure 2–7)

Upon the binding of two ligands individually and the dimerization of two receptors, the tyrosine kinase is activated and phosphorylate the dimerized receptor and the downstream signaling proteins. Example ligands include epidermal growth factor (EGF) and insulin.

However, the ability of receptors working with tyrosine kinase is limited by one process called “down-regulation”. After some time of continuous binding of ligands, the receptors will undergo endocytosis by the cell and thus reduce the expression of the transmembrane receptors. This is a natural process to control growth and differentiation. However, when genetic mutation happens and the down-regulation goes wrong, cancer happens due to overexpression of the receptors. Inhibitors for these receptors (e.g. EGF receptor inhibitors) or for the tyrosine kinase (e.g. tyrosine kinase inhibitors) have been an active field in cancer therapeutics research.

Ligand-regulated ion channels

Figure 4 (Testbook: Figure 2–9)

Ion channels are important for muscle contraction and relaxation. For example, cardiac muscles need to contract to pump the blood to the body.

Nicotinic acetylcholine receptor (nAChR) is a typical example of ion channels. The binding of ACh on the receptor causes the opening of the channel and therefore sodium (Na+) flows from the extracellular space into cells, leading to depolarization and muscle contraction. Other ligands for ion channels are serotonin, GABA, and glutamate, etc.

Voltage-gated ion channel

Not all ion channels are controlled by ligands. Voltage-gated ion channels are mediated by the membrane potential detected by the “voltage sensor”. Drugs target this type of channel typically bind to another side and inhibits the ion conduction separately from the voltage sensor. One typical example is verapamil, a calcium channel blocker.

Ligand-regulated transmembrane enzymes with G protein

Figure 5 (Testbook: Figure 2–5)

Receptors coupled with GTP-binding proteins (GTP proteins) are called “G protein-coupled receptors” (GPCRs). This is a largest family of receptors in human bodies and is characterized for its “seven-transmembrane” (7TM) structure.

Figure 6 (Testbook: Figure 2–11)

There are a few steps for G protein to execute its effect. First, an extracellular ligand binds to the receptor, and the binding activates the G protein in the cytoplasm. G protein changes the activity of effector elements (e.g. enzymes), and the effector elements changes the concentration of intracellular second messengers which are responsible for the following mechanisms.

There are many types of G proteins, effector elements, and second messengers. One common example is Gs protein, which stimulates the effector element, adenylyl cyclase which converts adenosine triphosphate (ATP) to cyclic adenosine-3′,5′- monophosphate (cAMP).

*Katzung B.G.(Ed.), (2017). Basic & Clinical Pharmacology, 14e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2249&sectionid=175215158