PLC IP3 Ca2+ Signaling Module

Phosphatidylinositol and PIP2

Phosphatidylinositol is a type of phospholipid found in phospholipid membranes.

Phosphatidylinositol consists of two acyl chains, a glycerol backbone, and a phosphoinositol head group.

The phosphoinositol head group can be phosphorylated by lipid kinases at the positions labeled 2, 3, 4, 5, and 6.

Phosphorylation of inositol at positions 4 and 5 generate phosphatidylinositol 4,5-bisphosphate, or PI(4,5)P2, which is often abbreviated to just PIP2.

Phospholipase C (PLC)

Phospholipase C, or PLC, is a membrane-associated enzyme that cleaves the bond between the glycerol and the phosphoinositol of PIP2.

The products of the reaction catalyzed by phospholipase C are diacylglycerol, or DAG, and inositol 1,4,5-triphosphate, or IP3.

The diacylglycerol remains associated with the membrane and can continue the signaling pathway.

IP3 is released into the cytosol and can bind to effector proteins to continue the signaling pathway.

IP3 and Calcium Release from ER

One of the effects of IP3 involves binding to IP3-gated calcium channels in the endoplasmic reticulum membrane.

Binding of four IP3 molecules opens the channel, which allows calcium stored in the ER lumen to enter the cytosol.

Calcium levels are typically low in the cytosol and high in the lumen of the endoplasmic reticulum and extracellular environment.

Signaling pathways lead to the opening of calcium channels in the plasma membrane and endoplasmic reticulum, resulting in an increase in cytosolic calcium levels.

Cytosolic calcium could have many diverse effects.

Calcium is removed from the cytosol by pumps in the ER and plasma membrane.

The level, localization, and dynamics of calcium release are complex and dependent on the characteristics of specific channels and pumps that are involved.

Protein Kinase C (PKC) Activation

Protein kinase C is activated and associates with membranes when bound to calcium and diacylglycerol.

Active protein kinase C can phosphorylate target proteins.

Calmodulin (CaM) and Calcium Signaling

Another effect of calcium is to bind to and activate a protein called calmodulin.

Four molecules of calcium bind to each molecule of calmodulin causing a conformational change.

The active form of calmodulin can bind to protein effectors, including calcium/calmodulin-dependent protein kinases.

Summary of PLC, IP3, Calcium Signaling

In summary, phospholipase C cleaves the phospholipid PIP2, generating IP3 and DAG.

IP3 opens calcium channels in the ER membrane, increasing cytosolic calcium levels

DAG and calcium activate protein kinase C which phosphorylates protein effectors.

Calcium binds calmodulin, which binds and regulates the activity of protein effectors