PIP2 second messenger

FIGURE 24.12 The PIP2 second-messenger scheme. When a hormone binds to a receptor, it activates phospholipase C, in a process mediated by a G protein. Phospholipase C hydrolyzes PIPj to IP3 and DAG. IP3 stimulates the release of Ca from intracellular reservoirs in the ER. A complex formed between Ca and the calcium-binding protein calmodulin activates a cytosolic protein kinase for phosphorylation of a target enzyme. DAG remains bound to the plasma membrane, where it activates the membrane-bound protein kinase C (PKC). PKC is involved in the phosphorylation-channel proteins that control the flow of Ca + in and out of the cell. Ca from extracellular sources can produce sustained responses even when the supply of Ca + in intracellular reservoirs is exhausted. 

Inositol trisphosphate Receptor/G-protein cascades. As discussed above, IP3 is one of the products of the hydrolysis of PIP2. To say that it acts as a second messenger means that a rise in its concentration occurs as a result of some meaningful event and that the rise causes some other significant event. In terms of information flow, the signal immediately preceding the rise in IP3 is a rise in the concentration of active PLC. This rise is due to the binding of a subset of G-proteins... 

The phospholipases (PLC) isozymes cleave the phosphodiester bond in phos-phatidyl-inositol-4,5-bisphosphate (PIP2) releasing two second messenger molecules inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) as shown before. The /1-isozyme are controlled by the Ga or G y subunits of the heterotrimeric G-proteins coupled to surface receptors. The y-isozymes are substrates for tyrosine kinases, such as growth factors. 

An additional phosphorylation (enzyme phosphatidylinositol-4-phosphate kinase 2.7.1.68) finally provides phosphaditylino-sitol-4,5-bisphosphate (PIP2, Ptdlns(4,5)P2). PIP2 is the precursor for the second messengers 2,3-diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsPa, IP3 see p. 367). 

Figure 14-3. Signaling through protein kinase C (PKC). Activated phospholipase C cleaves the inositol phospholipid PIP2 to form both soluble (IP3) and membrane-associated (DAG) second messengers. DAG recruits PKC to the membrane, where binding of calcium ions to PKC fully activates it. To accomplish this, IP3 promotes a transient increase of intracellular concentration by binding to a receptor on the endoplasmic reticulum, which opens a channel allowing release of stored calcium ions. PIP2, phosphatidylinositol 4,5-bisphosphate DAG, diacylglycerol PLC, phospholipase C IP3, inositol trisphosphate.

In recent years, research on the molecular mechanisms underlying lithium s therapeutic effects has focused on intracellular second messenger generating systems and, in particular, receptor-coupled hydrolysis of phosphoinositide 4,5-biphosphate (PIP2) (Baraban et al. 1989). Lithium, at therapeutically relevant concentrations in the brain, is a potent inhibitor of the intracellular enzyme, inositol monophosphatase [Kj = 0.8 mM), which plays a major role in... 

I nositol is a simple substance present normally in the diet at about 1 g/day and is an isomer of glucose. The phosphatidylinositol (PI) cycle is an important second messenger system for several brain neurotransmitters (Figure 9-1). Receptor (R) stimulation by an activator (A) leads to breakdown of membrane phosphatidylinositol 4,5-biphosphate (PIP2) to... 

The last three sources are transported into the cell via inositol transporter [T]. Inositol combines with cytidine monophosphate phosphatidic acid [GMPPA] to be converted to PI, which is then phosphorylated to phos-phatidylinositol phosphate [PIP] and to PIP2 to be reused to form the PI cycle-derived second messengers IP3 and DAG [Kofman and Belmaker 1993]. 

Phosphatidylinositol-4,5-bisphosphate (PIP2) and the two second messengers, diacylglycerol and inositol trisphosphate, that are derived from it. 

Effect of lithium on the IP3 and DAG second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP2, phosphatidylinositol-4,5-bisphosphate PLC, phospholipase-C G, coupling protein EFFECTS, activation of protein kinase C, mobilization of intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositol substrates, may cause... 

Fig. 5.2 Early G-protein signaling events at the AT]R. Phospholipases C and D are sequentially activated by heterotrimeric G-protein subunits to produce important second messengers such as IP3 and DAG. See text for details. ATiR, angiotensin II type 1 receptor DAG, diacylglycerol IP3, inositol 1,4,5-trisphosphate PA, phosphatidic acid PC, phosphatidylcholine PIP2, phosphatidylinositol-4,5-bisphosphate PKC, protein kinase C PLC, phospholipase C PLD, phospholipase D.

Fig. 1. A compact visual summary of the signaling of cytoplasmic/nuclear and cell surface receptors. ER, endoplasmic reticulum M, mitochondrion PIP2, phosphatidylinositol-4,5-diphosphate IP3, inositol triphosphate PK, protein kinase, second messenger.

---