Lecture 22: Cell Signaling

Cell Signaling

• how cells in a multicellular organism communicate using signaling molecules (ligands) that bind to specific receptors

• A ligand binds a receptor → signal is transduced → cellular response occurs

• Cells only respond if they express the correct receptor.

Signal Transduction

• amplifies the response to a signal

Ligand

• like a hormone or neurotransmitter

• binds to a specific receptor protein

  • causes conformational change in receptor, and activation of intracellular signaling pathways

Second Messengers

• intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules (first messengers)

• spread and amplify the message in the cell

Receptors

• 4 different types based on ____

  • Ligand-gated ion channel

  • GPCR

  • Enzyme-coupled receptor

  • Nuclear receptor

GPCR

• g-protein coupled membrane receptors

  • act via hydrolysis of GTP

• GPCR molecules bind to their ligands, then transmit their signal across the membrane to heterotrimeric G proteins

  • when GPCR binds it ligand, it binds and activates the G protein

  • the activated G protein then triggers a cascade of signals inside the cell

G Proteins

• 3 subunits:

  • α subunit

  • β subunit

  • γ subunit

• once activated via GPCR-ligand bind, it only remains active for a very short period of time

  • within this period, it can initiate either…

    • cAMP / PKA Pathway

    • IP₃ / Ca²⁺ Pathway

GPCR Activation Cycle

1. Ligand binds GPCR

2. GPCR activates G protein

3. GDP → GTP on α subunit

4. G protein dissociates

5. Activated subunits trigger downstream signaling

6. GTP is hydrolyzed → G protein inactivates

cAMP/PKA Pathway

1. GPCR activates G protein

2. G protein activates adenylyl cyclase

3. Adenylyl cyclase converts ATP → cAMP (a secondary messenger)

4. cAMP activates Protein Kinase A (PKA)

IP₃ / Ca²⁺ Pathway

1. GPCR activates G protein

2. G protein activates Phospholipase C (PLC)

3. PLC cleaves PIP₂ into:

   • DAG

   • IP₃

4. IP₃ diffuses to ER

5. IP₃ binds IP₃ receptor (ligand-gated Ca²⁺ channel)

6. Ca²⁺ released into cytosol

Enzyme Coupled Receptors

• Receptors with intrinsic enzymatic activity

• activation induces a conformation change, exposing the kinases

Tyrosine Kinase Receptor

1. Ligand binds receptor

2. Receptors dimerize

3. Kinase domains activate

4. Tyrosine residues phosphorylated

5. Phosphorylated sites recruit signaling proteins

Insulin Receptor

• example of a tyrosine kinase receptor

• Insulin binding activates:

  • Cytoplasmic tyrosine kinase domains

• Uses ATP

Steroid Hormone

• lipids which act as nuclear or cytoplasmic receptors

• Can cross plasma membrane

• Bind:

  • Cytoplasmic receptors

  • Nuclear receptors

Nuclear Receptors

• ligand–receptor complex:

  • Enters nucleus (or already there)

  • Directly binds to DNA

• Acts as a transcription factor and alters gene expression

Ecdysone

• Steroid hormone in insects which controls molting

• Binds nuclear receptor

• Activates gene transcription