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22.7: IP3/DAG Signaling Pathway
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Cell Biology

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IP3/DAG Signaling Pathway
 
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22.7: IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second messengers—a membrane-bound diacylglycerol (DAG) and a cytosolic inositol-1,4,5 trisphosphate (IP3). The events mediated by these second messengers are called IP3/DAG pathway.

IP3 is a sugar-phosphate molecule. They are soluble and can rapidly diffuse through the cytosol to reach the endoplasmic reticulum (ER). IP3 binds and opens IP3-gated calcium channels on the ER membrane and drives out calcium into the cytosol. This way, IP3 transmits an external signal by increasing the cytosolic concentration of another second messenger, like the calcium ions. IP3 triggers various cellular responses via elevating cytosolic calcium levels, including smooth muscle contraction in the blood vessels and platelet aggregation. However, IP3 also controls the rising cytosolic calcium levels. IP3 is rapidly degraded to inositol-1,4 bisphosphate, which cannot bind or open ER calcium channels. This prevents calcium release to the cytosol.

The second product, the membrane-bound second messenger DAG also plays an essential role in various cellular processes. They bind and activate protein kinase C (PKC), which is involved in cellular growth and metabolism. PKC phosphorylates multiple transcription factors, which move to the nucleus and initiate the transcription of genes involved in cell division.

DAG can also be cleaved to form arachidonic acid,  a precursor for eicosanoids, a small lipid signal molecule. A commonly known eicosanoid, prostaglandin, affects pain and inflammatory responses. Many anti-inflammatory and pain-relieving drugs available commercially, like aspirin, ibuprofen, and cortisone, inhibit prostaglandins synthesis.


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IP3 DAG Signaling Pathway Phosphatidylinositol Membrane Lipids Second Messengers Phosphorylated Inositol Phospholipids Phosphatidylinositol-4,5 Bisphosphate GPCR Gq Proteins Phospholipase C Diacylglycerol Cytosolic Inositol-1,4,5 Trisphosphate IP3/DAG Pathway Calcium Ions Endoplasmic Reticulum (ER) IP3-gated Calcium Channels Cytosolic Calcium Levels

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