Signaling by Inositol Phospholipids

When bound by nerve growth factor (NGF), the high affinity NGF receptor, TrkA, autophosphorylates tyrosine residues in its cytoplasmic domain. The activated receptor binds to and activates phospholipase Cg (PLCg), which cleaves membrane-bound phosphatidylinositol-bisphosphate (PIP₂) to generate D-myo-inositol-1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ diffuses from the plasma membrane to its receptor on the surface of the endoplasmic reticulum (ER) that is coupled to a Ca²⁺-release channel in the ER membrane. There it stimulates the release of Ca²⁺ from ER stores resulting in an increase in the cytosolic concentration of Ca²⁺. Cytosolic Ca²⁺ is then available for binding to calmodulin or to various Ca²⁺-binding cytoskeletal proteins involved in microtubule and intermediate filament formation. Many of the enzymatic effects of the released Ca²⁺ are mediated through protein phosphorylations catalyzed by a family of Ca²⁺/calmodulin dependent protein kinases (CaMK-II/IV).

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References:

Carpenter, G., and Ji, Q.S., Phospholipase Cg as a signal-transducing element. Exp. Cell Res., 253, 15-24 (1999).

Patel, S., et al., Molecular properties of inositol 1,4,5-trisphosphate receptors. Cell Calcium, 25, 247-264 (1999).

Takei, K., et al., Regulation of nerve growth mediated by inositol 1,4,5-trisphosphate receptors in growth cones. Science, 282, 1705-1708 (1998).