Lesson 6: GPCR Signaling and Second Messengers

Overview of Signaling Through GPCRs

• GPCRs target three key effectors for second messenger production:
  • Adenylyl cyclase (AC) → cyclic adenosine monophosphate (cAMP).
  • Phospholipase C (PLC) → inositol triphosphate (IP3) and diacylglycerol (DAG).
  • Phospholipase A2 (PLA2) → eicosanoids (20-carbon lipid mediators).

Second Messenger Characteristics

• Second messenger effects are tissue-specific, leading to varied responses in different cell types.
• cAMP regulates intracellular signal transduction through activating PKA (Protein Kinase A).

Enzymes and Their Functions

• Adenylyl Cyclase (AC): Converts ATP to cAMP.

  • Gs stimulates AC; Gi inhibits it.

• Phospholipase C (PLC): Converts PIP2 to IP3 and DAG.

  • Activates PLC involves Gq/11 and Ca+2; IP3 releases Ca+2 from endoplasmic reticulum (ER).

• Phospholipase A2 (PLA2): Liberates arachidonic acid, a precursor for various lipid signaling molecules (eicosanoids).

  • Eicosanoids include prostaglandins, thromboxanes, and leukotrienes.

Mechanism of Action of Second Messengers

• cAMP activates PKA to modulate protein function via phosphorylation (Ser/Thr residues).
• DAG activates PKC and is involved in cell growth, immune response, and more.
• IP3 triggers calcium release from ER, increasing intracellular [Ca+2].

Calcium Signaling

• Ca+2 is a versatile second messenger; involved in various cellular processes.
• Intracellular Ca+2 comes from extracellular sources or storage. Signals are terminated by pumps and transporters.

Ca+2-Calmodulin Signaling

• Calmodulin binds Ca+2, leading to conformational changes and activating downstream targets like NOS and various kinases.