(2B) Pharmacodynamics: Receptors II – G-protein coupled and tyrosine kinase

• Tyrosine =

• Kinase =

• Tyrosine = amino acid.

• Kinase = enzyme that transfers phosphate to a substrate.

Receptor tyrosine kinase (RTK) =

Receptor tyrosine kinase (RTK) = membrane-anchored receptor with intrinsic kinase activity.

Receptor tyrosine kinase (RTK)

Structure

• Single transmembrane helix

• Extracellular domain → ligand binding

• Intracellular kinase domain → phosphorylation

Structure

GPCR vs. RTK

GPCR	RTK
7 transmembrane regions	1 transmembrane helix
Signals through G proteins	Has intracellular kinase activity - phosphorylation

• Monomer =

• Dimer =

• Phosphorylation =

• Monomer = 1 receptor

• Dimer = 2 receptors

• Phosphorylation = signal that the receptor has been activated

RTK Activation is mainly what?

Dimerization + Phosphorylation

RTK Activation - main mechanism:

Before ligand binds

1 receptor alone = monomer

Then:

Ligand binds
→ receptor changes shape
→ 2 receptors come together = dimer
→ the 2 receptors add phosphate groups to each other
→ receptor is activated
→ proteins inside the cell recognize the activated receptor
→ intracellular signaling starts
→ cellular response

Simplest version:

Ligand → dimerization → phosphorylation → intracellular signaling → response

RTK examples talked about?

• Insulin

• Growth

RTK and Insulin?

• Insulin

  • Meal

    • ↑ blood glucose

    • insulin released outside the cell

    • binds RTK

    • starts phosphorylation/signaling inside the cell

Professor connected insulin with:

• muscle cells

• liver cells

• glucose handling

• anabolic/growth effects

RTKs and Growth

RTK signaling can affect:

• cell growth

• cell proliferation

• cell survival

• differentiation

• blood-vessel growth

That is why RTKs are especially important in:

• endocrine pharmacology

• cancer pharmacology

Abnormally active growth signaling can contribute to cancer.

What Happens After RTK Activation/Phosphorylation?

• → intracellular pathway activated → specific cellular effect

• Some RTK pathways can eventually reach the nucleus:

  • RTK activated

    • intracellular signaling

    • nucleus

    • change gene expression

    • change protein production

RTK activated → intracellular pathway activated → specific cellular effect

What are the main pathways shown?

Pathway	Main Result
Ras/MAPK	Cell growth/proliferation + differentiation
PI3K/Akt	Cell survival + metabolism
PLCγ	IP₃/DAG + Ca²⁺ signaling
STAT	Gene transcription

example of a drug that blocks abnormal tyrosine kinase activity/ tyrosine kinase inhibitor.

Imatinib / Gleevec

Explain what happens after blocking an overactive tyrosine kinase?

 stop/reduce the growth signaling and treats the disease

Membrane receptors vs. Intracellular receptors

Membrane receptors → faster

Intracellular receptors → slower because they change gene expression.

Give example of Membrane Receptor Response?

Stress
→ epinephrine
→ membrane receptor
→ heart rate changes within seconds