Phospholipase C: IP3 - DAG Pathway
Seen downstream of Gq Protein-coupled receptors.
Gq protein is composed of 3 subunits: Ī±, Ī², and Ī³.
Resting Condition
Trimer of Ī±, Ī², and Ī³ subunit is associated with the receptor.
Ī± subunit is bound to GDP.
Activation and Signaling
Formation of IP3 and DAG
Ligand binds with the receptor
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Conformational change
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Release of GDP and binding of GTP to Ī± subunit
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Dissociation of the complex from receptor & separation of subunits
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Formation of free Ī± subunit and Ī²Ī³ complex
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Ī± subunit travels along the membrane
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Goes to a membrane-bound enzyme, phospholipase C
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Ī± subunit activates phospholipase C
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Phospholipase C breaks down a membrane phospholipid, PIP2 (phosphatidylinositol 4,5 bis-phosphate)
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Formation of:
IP3 (inositol 1,4,5-tris-phosphate) &
DAG (diacylglycerol)
Effects downstream of IP3
IP3 is water-soluble
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Travels through the cytosol
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Binds with calcium channel on endoplasmic reticulum
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Opening of the channel
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Release of calcium from the endoplasmic reticulum into the cytosol
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Calcium binds with various calcium-binding proteins for example calmodulin
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Formation of Calcium-Calmodulin complex
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Modulates the activity of Calcium-Calmodulin dependent kinases (CaM kinases) for example activation of Myosin Light Chain Kinase (MLCK) in smooth muscle cell
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Smooth muscle contraction
Other effects of increased calcium level:
Glandular secretion.
Transmitter release.
Eicosanoid synthesis.
Cell proliferation, etc.
Effects downstream of DAG
DAG
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Activates Protein Kinase C (PKC)
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PKC Phosphorylates various proteins and modulates their activity.
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Different responses in different cells
For example:
Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) proteins contribute to changing cell shape.
Transcription factors affect gene expression.
Termination of the Signal
Ī± subunit
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has GTPase activity
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Hydrolyses GTP into GDP and inorganic phosphate
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Inactive Ī± subunit
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Reassociates with Ī²Ī³ complex
IP3
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Dephosphorylated
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Formation of inositol
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Reutilized in the synthesis of PIP2
DAG
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Converted to phospholipids
Calcium
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Pumped back into the endoplasmic reticulum or out of the cell
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Downstream activity decreases
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