Lecture Notes on Adenylyl Cyclase: cAMP Pathway

Summary:

In this lecture, we explored the adenylyl cyclase: cAMP pathway, which is a key mechanism of intracellular signaling, influenced by Gs and Gi proteins of G protein-coupled receptors (GPCRs). Activation of Gs proteins increases cellular activities while Gi proteins decrease them through modulation of the adenylyl cyclase enzyme.

Adenylyl Cyclase: cAMP Pathway

Gs Protein-Coupled Receptor Activation

• Structure and Activation:
  • Gs protein consists of αs, β, and γ subunits.
  • Under resting state, the trimer is bound to GDP and associated with the receptor.
  • Ligand binding induces GTP binding in place of GDP, disassociating αs from βγ.
• Function:
  • The αs subunit activates adenylyl cyclase, a membrane-bound enzyme facing the cytosol.
  • Adenylyl cyclase converts ATP into cyclic AMP (cAMP).
  • Increased cAMP activates Protein Kinase A (PKA), which then phosphorylates various proteins affecting cellular functions.
• Examples:
  • Cardiac Myocytes: Stimulation by adrenaline through β1 receptors increases contractility.
  • Liver Cells: Stimulation by glucagon through glucagon receptors enhances glycogen breakdown into glucose.

Pathway Termination

• GTPase Activity:
  • α subunit hydrolyzes GTP to GDP, reassociating with βγ and inactivating adenylyl cyclase.
• Cyclic AMP Degradation:
  • Phosphodiesterase converts cAMP to AMP, reducing PKA activity.
• Protein Dephosphorylation:
  • Protein phosphatases reverse phosphorylation of target proteins, ending the signal transduction.

Gi Protein-Coupled Receptor Activation

• Structure and Activation:
  • Similar structure to Gs with αi, β, and γ subunits.
  • Ligand binding leads to GTP binding, disassociating αi which then inhibits adenylyl cyclase.
• Function:
  • Inhibition of adenylyl cyclase by αi decreases cellular activity.
• Examples:
  • SA Node Cells: Activation by acetylcholine through M2 receptors decreases heart rate.
  • Pancreatic β cells: Stimulation by adrenaline through α2 receptors decreases insulin release.

Functional Integration in a Single Cell

• Cells expressing both Gs and Gi proteins can modulate activity dynamically based on receptor stimulation.
• Example:
  • Cardiac Myocytes:
    • β1 receptors (Gs protein-coupled) increase cAMP and contractility.
    • M1 receptors (Gi protein-coupled) decrease cAMP and contractility.
  • The balance of sympathetic and parasympathetic inputs determines overall cardiac output.

Conclusion:

This pathway illustrates how second messenger systems like cAMP can integrate varying extracellular signals (e.g., adrenaline and acetylcholine) to finely regulate cellular functions like contractility. The dynamic between Gs and Gi coupling provides a robust mechanism for cellular response modulation.

Notes for Further Studies:

• Consider exploring how different ligands specificity affect Gs and Gi pathway activations.
• Study the pathological implications when these pathways are dysregulated.

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