1-2 Pharmacodynamics

Question 1

What are the molecular targets of drugs?

Answer 1

Receptors

Enzymes

Transport proteins

Voltage-dependent ion channels

Others…

Question 2

What do receptors mediate?

Answer 2

They mediate:

• Neurotransmitters
• Eicosanoids
• Hormones
• Pharmacons

Question 3

What are the types of receptors?

Answer 3

IC receptors

Ligand-regulated transmembrane receptors

Transmembrane ligand-gated ion channels

G protein coupled receptors

Question 4

Intracellular receptors!

Answer 4

The ligand must diffuse into the cell to interact with the receptor. To diffuse through it must have sufficient lipid solubility. They usually affect transcription factors in the cell nucleus, which upregulates or downregulates the transcription of certain DNAs.

The time course of activation of these receptors: hours-days.

Intracellular ligands can also target structural proteins, enzymes, RNA and ribosomes.

• Nuclear receptors (T3): e.g. thyroid hormone receptor
• Cytoplasmic receptors:
  
  • Translocated into the nucleus (steroids, vitamin D, retinoids, PPAR, lipid sensors)
  • Remain in the cytoplasm: e.g. Ryanodine receptor (e.g. Dantrolen), IP3 receptor

Question 5

Ligand-regulated transmembrane receptors!

Answer 5

• These receptors consist of a protein that spans the membrane once and may form dimers or multisubunit complexes.
• They have cytosolic enzyme activity as an integral component of their structure and function
• Binding of a ligand to the EC domain will either activates or inhibits the activity of the enzyme
  
  • Metabolism, growth, and differentiation are important biological functions controlled by these receptors
• Tyrosine-kinase-coupled: insulin, growth factor
• JAK-coupled: cytokines

Question 6

Transmembrane ligand-gated ion channels

Answer 6

The most common one is the nicotinic receptor made of different units: a, b, d, g.

e.g.:

• Serotonin receptor 3 (only) is ionotropic
• AMPA receptor
• Glycine receptor
• GABA_A receptor: allosteric binding sites are present to modify the effect of the NT
• NMDA receptor

Question 7

G-protein coupled receptors!

Answer 7

• The extracellular part contains the ligand-binding site
• The intracellular part interacts with the G proteins. It is composed of 3 subunits:
  
  • a subunit: binds GTP
  • b and g subunits: anchor the G protein in the cell membrane
• Binding of ligand leads to dissociation of a-GTP complex from bg-complex.
  
  • These 2 complexes can interact with other cellular effectors (enzymes, proteins) –> 2^nd messenger –> signaling cascade!
• When activated, we have different consequences depending on the type of receptor:
  
  • G_i: inhibitory ==> reducedcAMP
  • G_s: stimulatory ==> increased­ cAMP
  • G_q: ==> increased­ DAG, IP₃

1. Class 1 (“A”) – Rhodopsin-like

• Muscarinic acetylcholine receptors (M_1-5)
• Biogenic amines EXCEPT 5-HT₃ (D_1-5; α_1A,B,D; α_2A,B; β_1-3; H_1-4; 5-HT_{1-2, 4-7})
• Majority of neuropeptide receptors (Opioid, Angiotensin, Bradykinin, CCK, NPY, Vasopressin/Oxytocin, etc)
• Glycoprotein hormone receptors (FSH, LH, TSH, stb)
• Adenosine, P2Y receptors
• Prostanoid, leukotriene and lipoxin receptors

1. Class 2 (“B”) – Secretin-R-like:

• Glucagon-secretin receptor family
• Calcitonin receptor family
• CRF receptor family
• PTH receptor family, etc.

1. Class 3 (“C”) – Metabotropic glu-R-like:
   * Metabotropic glutamate receptors (mGlu 1-7)

GABA B receptors