Adenylyl Cyclase-cAMP Pathway of Intracellular Signaling

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Adenylyl Cyclase: cAMP Pathway

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

Gs protein

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Stimulates the pathway

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Usually increases the activity of the cell

Gi Protein

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inhibits the pathway

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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

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Conformational change

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Release of GDP and binding of GTP to αs subunit

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Dissociation of the complex from receptor & separation of subunits

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Formation of free αs subunit and βγ complex

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αs subunit travels along the membrane

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Goes to the membrane-bound enzyme adenylyl cyclase

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Activates adenylyl cyclase

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Adenylyl cyclase converts ATPs into cAMPs

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Increased concentration of cAMP

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Activation of cAMP-dependent Protein Kinase A (PKA)

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

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Change in the activity of phosphorylated protein

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Response of the cell

For example in myocardial cells:

Adrenaline

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Activates β1 receptor which is a Gs protein-coupled receptor

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Activation of the cAMP pathway as explained above

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Phosphorylation of transport proteins on sarcoplasmic reticulum

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Increases sequestration of calcium in sarcoplasmic reticulum

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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

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Hydrolyses GTP into GDP and inorganic phosphate

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Inactive αs subunit

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Dissociates from the adenylyl cyclase

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Prevents further activity of adenylyl cyclase

Inactivation of cAMP and PKA:

Phosphodiesterase enzyme

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Converts cAMP into AMP

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Decreased concentration of cAMP

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Prevents further activity of PKA

Inactivation of the target protein:

Various protein phosphatase enzymes

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Cause dephosphorylation of target proteins

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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

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

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Baseline activity of adenylyl cyclase is prevented

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Activity of the cell decreases

For example in SA node:

Acetylcholine

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Activates M2 receptor which is a Gi protein coupted receptor

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Stimulation of Gi protein

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Formation of αi subunit

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Inhibits baseline activity of adenylyl cyclase

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Decreased impulse generation at SA node

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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

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Release adrenaline

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Stimulates β1 receptor

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Activation of Gs protein

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Increased activity of adenylyl cyclase

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Increased contractility

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Increased cardiac output

Parasympathetic Nerves

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Release acetylcholine

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Stimulates M2 receptors

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Activation of Gi protein

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Decreased activity of adenylyl cyclase

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Decreased contractility

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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.