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Adenylyl Cyclase: cAMP Pathway



This pathway is seen downstream of Gs and Gi protein-coupled receptors.

Gs protein

Stimulates the pathway

Usually increases the activity of the cell


Gi Protein

inhibits the pathway

Usually decreases the activity of the cell


Gs Protein Pathway

  • Gs protein is composed of 3 subunits: αs, β and γ.

Resting Condition
  • Trimer of αs, β and γ subunit is associated with the receptor.

  • αs subunit is bound to GDP.

Activation and Signaling

Ligand binds with the receptor

Conformational change

Release of GDP and binding of GTP to αs subunit

Dissociation of the complex from receptor & separation of subunits

Formation of free αs subunit and βγ complex

αs subunit travels along the membrane

Goes to the membrane-bound enzyme adenylyl cyclase

Activates adenylyl cyclase

Adenylyl cyclase converts ATPs into cAMPs

Increased concentration of cAMP

Activation of cAMP-dependent Protein Kinase A (PKA)

PKA phosphorylates different transport proteins, metabolic enzymes, transcription factors, or structural proteins

Change in the activity of phosphorylated protein

Response of the cell


For example in myocardial cells:

Adrenaline

Activates β1 receptor which is a Gs protein-coupled receptor

Activation of the cAMP pathway as explained above

Phosphorylation of transport proteins on sarcoplasmic reticulum

Increases sequestration of calcium in sarcoplasmic reticulum

Increased contractility of cardiac myocyte


Termination of the Signal
  • When external stimulation is no longer present ⟶ intracellular signal is terminated.

  • Occurs at multiple levels as follow:

Inactivation of αs subunit and adenylyl cyclase:

αs subunit has GTPase activity

Hydrolyses GTP into GDP and inorganic phosphate

Inactive αs subunit

Dissociates from the adenylyl cyclase

Prevents further activity of adenylyl cyclase


Inactivation of cAMP and PKA:

Phosphodiesterase enzyme

Converts cAMP into AMP

Decreased concentration of cAMP

Prevents further activity of PKA


Inactivation of the target protein:

Various protein phosphatase enzymes

Cause dephosphorylation of target proteins

Reverses the activity of the target proteins


Gi Protein Pathway

  • Gi protein is composed of 3 subunits: αi, β and γ.

Follows a similar path as explained above

But instead of stimulating, αi in this case inhibits adenylyl cyclase

Baseline activity of adenylyl cyclase is prevented

Activity of the cell decreases


For example in SA node:

Acetylcholine

Activates M2 receptor which is a Gi protein coupted receptor

Stimulation of Gi protein

Formation of αi subunit

Inhibits baseline activity of adenylyl cyclase

Decreased impulse generation at SA node

Fall in heart rate


Gs and Gi Together in the Same Cell

  • Presence of Gs and Gi in the same cell provides an opportunity to stimulate or inhibit the same activity.

    • Gs protein stimulates the activity.

    • Gi protein inhibits the activity.

For example, Cardiac Myocytes:
  • Have:

    • β1 receptors, a Gs protein-coupled receptor.

    • M2 receptor, a Gi protein-coupled receptor.

Sympathetic Nerves

Release adrenaline

Stimulates β1 receptor

Activation of Gs protein

Increased activity of adenylyl cyclase

Increased contractility

Increased cardiac output



Parasympathetic Nerves

Release acetylcholine

Stimulates M2 receptors

Activation of Gi protein

Decreased activity of adenylyl cyclase

Decreased contractility

Decreased cardiac output


  • This is a great example of how a second messenger system integrates signals from different extracellular messengers to control a single cellular function.

 

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