Adenylate Cyclase cAMP Pathway of Intracellular Signaling

G Protein-Coupled Receptors (GPCRs)

Two important G proteins: Gs and Gi
- Gs: Stimulates adenylate cyclase, increases cell activity
- Gi: Inhibits adenylate cyclase, decreases cell activity

Structure: Alpha-s, beta, and gamma subunits
Resting State:
- Trimer associated with receptor
- Alpha subunit bound to GDP
Activation:
- Ligand binds, causing conformational changes
- GDP released, GTP binds
- Alpha subunit dissociates from beta-gamma complex
Pathway Activation:
- Alpha-s travels to adenylate cyclase (membrane-bound enzyme)
- Adenylate cyclase converts ATP to cyclic AMP (cAMP)
- cAMP activates Protein Kinase A (PKA)
- PKA phosphorylates various proteins, modulating activity
Examples:
- Myocardial Cells:
  - Beta-1 receptors activated by adrenaline
  - Increases contractility of cardiac myocytes
- Liver Cells:
  - Glucagon receptors activated by glucagon
  - Leads to glycogenolysis and glucose release

Alpha Subunit:
- GTPase activity hydrolyzes GTP to GDP
- Re-associates with beta-gamma complex
cAMP:
- Phosphodiesterase converts cAMP to AMP
Target Proteins:
- Protein phosphatases dephosphorylate proteins

Structure: Alpha-i, beta, and gamma subunits
Activation:
- Similar process as Gs proteins
- Alpha-i inhibits adenylate cyclase
- Results in decreased cellular activity
Examples:
- SA Node:
  - M2 receptors activated by acetylcholine
  - Decreases heart rate
- Pancreatic Beta Cells:
  - Alpha-2 adrenergic receptors activated by adrenaline
  - Decreases insulin release

Presence of both provides control over cellular functions
Example: Cardiac myocytes
- Beta-1 receptors (Gs): Increase cAMP, increase contractility
- M2 receptors (Gi): Decrease cAMP, decrease contractility

Gs Pathway:
- Alpha subunit activates adenylate cyclase, increases cAMP
- PKA activation, phosphorylation of proteins, increased activity
- Signal termination through GTPase, phosphodiesterase, and phosphatases
Gi Pathway:
- Inhibits adenylate cyclase, decreases activity