22.7:
IP3/DAG Signaling Pathway
Membrane phospholipids such as phosphatidylinositol 4,5-bisphosphate or PIP2, present on the cytosolic side of the membrane, function as precursors of important second messengers.
Ligand-bound GPCR recruits and stimulates Gq proteins. G-α-q subunit detaches from the receptor and activates a membrane-bound enzyme, phospholipase C-ꞵ or PLC-ꞵ.
PLC-ꞵ hydrolyzes PIP2 to yield two second messengers, a membrane-bound 1,2-diacylglycerol or DAG, and diffusible inositol 1,4,5-trisphosphate or IP3.
IP3 binds and opens IP3-gated calcium channels on the endoplasmic reticulum membrane, releasing calcium ions in the cytosol.
Increasing cytosolic calcium allows protein kinase C or PKC to translocate to the plasma membrane. It is activated by the membrane-bound DAG to phosphorylate different target proteins.
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.
Suggested Reading
- Alberts, Bruce, et al. Molecular Biology of the Cell. 6th ed. Garland Science, 2017. pp836-38
- Karp, Gerald. Cell and Molecular Biology: Concepts and Experiments. 6th ed. John Wiley & Sons, 2010. pp 616-17
- Lodish, Harvey, et al. Molecular Cell Biology. 8th ed. W.H. Freeman and Company, 2016. Pp709-12