IP3 Signaling

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IP3 Signaling

• Caroline Runyan
• Dec. 10, 2003

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The Basic Mechanism
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Molecular PlayersPhosphatidylinositol (PI)

• Membrane Component
• Synthesized in Endoplasmic Reticulum
• Cellular Roles
• PLC Substrate
• Protein Recruitment to the Membrane
• Via pleckstrin homology (PH) domains
• Ex PLC
• Ex Profilin

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Molecular PlayersProfilin

• Actin-binding protein
• Actin polymerization
• Cell Motility
• While bound to PI
• Sequestered from actin monomers
• Prevents unactivated-PLC- d -mediated PI
  Hydrolysis

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Molecular PlayersPI-Specific Phospholipase C
(PLC)

• Cleaves PI to produce Inositol Triphosphate (IP3)
  and Diacylglycerol (DAG)
• Four main groups
• a, ß, ?, d
• PLC- ß
• Most abundant in the brain
• Regulated by G-Proteins
• Inhibited by Protein Kinase C (PKC)
• Negative Feedback Inhibition

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Molecular PlayersPLC-cont.

• PLC- d
• Found throughout the body
• Inhibited by Profilin
• Compete for PI binding
• Inhibited by IP3
• Negative Feedback Mechanism

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Molecular PlayersIP3

• Known to interact with two types of proteins
• ER-IP3 Receptors
• Inducing release of sequestered Calcium
• Metabolizing Enzymes
• Huge group of diverse proteins, implying
  diversity of function

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Molecular PlayersProtein Kinase C (PKC)

• DAG Product
• Regulated by Ca2, Phosphatidylserine, DAG
• Substrates
• Receptors, Channels, Kinases, Cytoskeletal
  proteins, Enzymes
• Widespread Effects

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Molecular PlayersArachidonic Acid (AA)

• DAG Product
• Activates PKC- d, various cationic channels, NMDA
  channels

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Pathway RegulationInteraction Between the Ca2
and PKC Branches

• Synergistic
• Platelets
• Antagonistic
• Neurons
• Independent
• Lymphocytes
• Temporal
• Pancreas

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Pathway RegulationNegative Feedback Inhibition

• PKC-Mediated
• Inhibits PLC
• Degrades active pathway products
• Desensitization
• Calcium-Mediated
• Interferes with IP3 binding at ER
• Alters PLC-Specificity

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Pathway RegulationPhospholipid-Mediated

• Phosphatidylcholine (PC)
• After prolonged IP3 pathway stimulation
• PKC activates PC-specific PLC and PLD
• Leads to production of DAG
• No more IP3 production
• Affects membrane fluidity
• cAMP production

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Clinical Implications

• Schizophrenia
• Abnormal phospholipid composition of the bilayer
  and the dopamine hypothesis.
• Group I mGlu Rs
• Bipolar Disorder
• Disruption later in pathway, involving PLC and/or
  phosphatidylinositol recovery.

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Summary

• Phosphatidylinositol is cleaved by PLC to form
  IP3 and DAG.
• IP3 diffusion through the cytosol results in ER
  release of Calcium.
• DAG activates PKC, which then mediates several
  processes throughout the cell.
• The pathway is regulated by its own products as
  well as surrounding molecules.
• Any abnormality in any of the molecules involved
  can have devastating effects.