4. Autocrine Signaling

• Cell signals itself
• Important in development and immune response

Reception

Receptors: Proteins that bind signal molecules (ligands)

Types:

1. Cell Surface Receptors

• For hydrophilic signals (can't cross membrane)
• G protein-coupled receptors (GPCRs)
• Receptor tyrosine kinases (RTKs)
• Ligand-gated ion channels

2. Intracellular Receptors

• For hydrophobic signals (can cross membrane)
• Located in cytoplasm or nucleus
• Examples: steroid hormones, thyroid hormones

Signal Transduction

Transduction: Converting signal into cellular response

Key mechanisms:

1. Protein Phosphorylation Cascades

• Protein kinases add phosphate groups
• Protein phosphatases remove phosphate groups
• Phosphorylation relay: chain of activated proteins
• Amplifies signal

2. Second Messengers

Small molecules that relay signals inside cell:

cAMP (cyclic AMP):

• Made from ATP by adenylyl cyclase
• Activates protein kinase A (PKA)
• Degraded by phosphodiesterase

Ca²⁺ (calcium ions):

• Stored in ER, released into cytoplasm
• Activates many proteins
• Important in muscle contraction, neurotransmitter release

IP₃ and DAG:

• Made from membrane phospholipids
• IP₃ triggers Ca²⁺ release
• DAG activates protein kinase C (PKC)

3. Signal Amplification

• One signal molecule activates many molecules
• Cascade effect
• Example: 1 epinephrine → billions of glucose molecules released

Response

Cellular responses:

• Gene expression changes
• Enzyme activation/inhibition
• Cell shape/movement changes
• Cell division
• Apoptosis (programmed cell death)

Regulation of Signaling

Termination mechanisms:

• Ligand dissociates from receptor
• Receptor inactivated or degraded
• Second messengers broken down
• Protein phosphatases remove phosphate groups

Feedback mechanisms:

• Negative feedback: response inhibits pathway
• Positive feedback: response enhances pathway

Key Concepts

1. Three stages: reception, transduction, response
2. Cell surface receptors for hydrophilic signals
3. Intracellular receptors for hydrophobic signals
4. Phosphorylation cascades transmit and amplify signals
5. Second messengers (cAMP, Ca²⁺) relay signals
6. Signal amplification allows small stimulus → large response
7. Feedback regulation controls signaling pathways

Specificity:

• Only cells with epinephrine receptors respond
• Different receptors (α, β) → different responses

(b) Transduction:

Definition: Signal converted to form that brings about cellular response

Epinephrine pathway (simplified):

Step 1: Epinephrine binds → receptor changes shape

Step 2: Activated receptor activates G protein

• G protein exchanges GDP for GTP
• G protein dissociates, activated

Step 3: G protein activates adenylyl cyclase (enzyme in membrane)

Step 4: Adenylyl cyclase converts ATP → cAMP (second messenger) $\text{ATP} \xrightarrow{\text{adenylyl cyclase}} \text{cAMP} + \text{PP}_i$

Step 5: cAMP activates protein kinase A (PKA)

• PKA normally inactive (regulatory + catalytic subunits)
• cAMP binds regulatory subunits → releases catalytic subunits
• Active PKA phosphorylates target proteins

Step 6: PKA activates phosphorylase kinase

Step 7: Phosphorylase kinase activates glycogen phosphorylase

(c) Response:

Definition: Transduced signal triggers specific cellular response

Epinephrine response:

Final enzyme: Glycogen phosphorylase $\text{Glycogen} \xrightarrow{\text{phosphorylase}} \text{Glucose-1-phosphate} \rightarrow \text{Glucose}$

Cellular response:

• Glycogen breakdown increases
• Glucose released into bloodstream
• Energy available for "fight or flight"

Signal Amplification:

Cascade effect - each step amplifies signal:

1 epinephrine molecule
    ↓
~100 G proteins activated
    ↓
~1,000 adenylyl cyclase molecules activated
    ↓
~10,000 cAMP molecules produced
    ↓
~10,000 PKA activated
    ↓
~100,000 phosphorylase kinase activated
    ↓
~1,000,000 glycogen phosphorylase activated
    ↓
~100,000,000 glucose molecules released!

Amplification factor: ~10⁸-fold (100 million)!

$\boxed{\text{1 signal molecule} \rightarrow 10^8 \text{ response molecules}}$

Termination:

• cAMP broken down by phosphodiesterase
• Removes second messenger
• PKA inactivated
• Signal stops

Why amplification matters:

• Small amount of hormone → large response
• Efficient use of signal molecules
• Allows rapid, massive cellular response

Other examples:

• Insulin: Promotes glucose uptake (tyrosine kinase receptor)
• Growth factors: Cell division (receptor tyrosine kinases)
• Neurotransmitters: Nerve impulse transmission (ligand-gated ion channels)