Cell Physiology/Part 3

📡Cell Signaling

Cells constantly communicate with each other and respond to their environment through sophisticated signaling pathways. Understanding signal transduction is essential for physiology, pharmacology, and understanding disease.

🔗 Signal Transduction: The Basics

Signal transduction converts an extracellular signal into an intracellular response through a cascade of molecular events. This process involves signal amplification, allowing a few signaling molecules to produce a large cellular response.

📨
1. Signal
Hormone, neurotransmitter, growth factor
🎯
2. Receptor
Binds signal with high specificity
⚙️
3. Transducers
G-proteins, kinases, second messengers
✨
4. Response
Enzyme activity, gene expression, behavior

🎯Major Receptor Types

Receptor TypeStructureMechanismSpeedExamples
Ion Channel (Ionotropic)Ligand-gated channelDirect ion flux~msnAChR, GABAA, NMDA
GPCR (Metabotropic)7-TM helixG-protein cascade~secβ-AR, mAChR, opioid
Tyrosine KinaseSingle-pass TMPhosphorylation~minInsulin-R, EGF-R, PDGF-R
Nuclear ReceptorIntracellularGene transcription~hoursSteroid-R, Thyroid-R, VDR
Cytokine ReceptorSingle-pass TMJAK-STAT pathway~minIL-R, IFN-R, GH-R

📡G-Protein Coupled Receptor (GPCR) Signaling Simulator

Plasma MembraneExtracellularLGPCRαβγGGsACcAMP0%PKAIntracellular

Cascade Status:

1. Ligand binding
2. G-protein activation
3. AC activation
4. PKA activation
Gs pathway: Epinephrine → β-adrenergic receptor → Gs → ↑cAMP → PKA activation → fight-or-flight response

🔄G-Protein Subfamilies

Gαs

Stimulates AC → ↑cAMP

β-adrenergic, glucagon, TSH

Gαi/o

Inhibits AC → ↓cAMP

M2 muscarinic, α2-adrenergic, opioid

Gαq/11

Activates PLC → IP₃ + DAG

α1-adrenergic, M1/M3 muscarinic

Gα12/13

Activates Rho → cytoskeleton

Thrombin, LPA

💬Second Messengers

cAMP

Cyclic AMP

Production: ATP → cAMP (Adenylyl cyclase)
Removal: cAMP → AMP (PDE)
Targets: PKA, EPAC, Ion channels (HCN)
Glycogenolysis, lipolysis, heart rate ↑

cGMP

Cyclic GMP

Production: GTP → cGMP (Guanylyl cyclase)
Removal: cGMP → GMP (PDE)
Targets: PKG, PDE, Ion channels (CNG)
Vasodilation, phototransduction

IP₃

Inositol 1,4,5-trisphosphate

Production: PIP₂ → IP₃ + DAG (PLC)
Removal: IP₃ → IP₂ (5-phosphatase)
Targets: IP₃R (ER Ca²⁺ channel)
Ca²⁺ release from ER

DAG

Diacylglycerol

Production: PIP₂ → IP₃ + DAG (PLC)
Removal: DAG → PA or MAG
Targets: PKC
Cell growth, secretion

Ca²⁺

Calcium ions

Production: Entry or ER release
Removal: PMCA, SERCA, NCX
Targets: Calmodulin → CaMK, PKC, Calcineurin
Contraction, secretion, gene expression

📈Signal Amplification Cascade

A key feature of signal transduction is amplification. One hormone molecule can trigger production of thousands of product molecules.

1 Hormone
1
→ 1 Receptor
1
→ G-proteins
~10
→ AC molecules
~100
→ cAMP
~1,000
→ PKA
~10,000
→ Phosphorylated targets
~100,000
Example: One molecule of epinephrine can activate the release of ~10,000 glucose molecules from glycogen within seconds!

🔬Receptor Tyrosine Kinases (RTKs)

Mechanism

  1. 1.Ligand binding causes receptor dimerization
  2. 2.Trans-autophosphorylation of tyrosine residues
  3. 3.Phosphotyrosines recruit SH2-domain proteins
  4. 4.Activation of downstream pathways (Ras/MAPK, PI3K/Akt)

Clinical Significance

  • •Insulin receptor: Diabetes mellitus
  • •EGFR: Cancer target (Herceptin, gefitinib)
  • •VEGFR: Angiogenesis, cancer therapy
  • •Bcr-Abl: CML (Gleevec/imatinib)

Chapter Topics

3.1

Receptor Types

Classification and mechanisms of cellular receptors

3.2

G-Protein Signaling

GPCR structure and G-protein activation cycles

3.3

Tyrosine Kinases

RTKs, JAK-STAT, and phosphorylation cascades

3.4

Second Messengers

cAMP, cGMP, IP₃, DAG, and calcium

3.5

Signal Integration

Crosstalk, feedback, and pathway convergence

←Part 2: Cellular EnergeticsPart 4: Muscle Physiology→