Second messengers inositol-1,4,5 trisphosphate

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

Rosel, P, Arranz, B., San, L. et al. Altered 5-HT2A binding sites and second messenger inositol trisphosphate (IP3) levels in hippocampus but not in frontal cortex from depressed suicide victims. Psych. Res. Neuroimag. 99 173-181,2000. 

Inositol is a hexahydric sugar alcohol. Its main function is in phospholipids phosphatidylinositol constitutes some 5% to 10% of the total membrane phospholipids. In addition to its structural role in membranes, phosphatidylinositol has a major function in the intracellular responses to peptide hormones and neurotransmitters, yielding two intracellular second messengers inositol trisphosphate and diacylglycerol. 

There are two major types of vasopressin receptors, VI and V2. The VI receptor occurs in vascular smooth muscle and is coupled via to activation of the phosphoinositide cascade-signaling system and generation of the second messenger inositol trisphosphate (IP3) and diacylglycerol. V2 receptors are found in kidney and are coupled via to activation of adenylate cyclase and production of the second messenger cyclic AMP. 

In addition to the mechanism involving cycHc AMP, nonsugar sweeteners, eg, saccharin and a guanidine-type sweetener, have been found to enhance the production of another second messenger, inositol 1,4,5-trisphosphate (IP3), causing the closure of potassium channels and the release of... 

Alternative second-messenger pathways may be at work in olfactory transduction. The role of cAMP in olfactory transduction is well established. Are there alternative pathways, such as those involving phospholipids and Ca2+ Several groups have reported that certain odorants can elicit an increase in the phosphoinositde second messenger inositol 1,4,5,-trisphosphate (IP3) (Ch. 20). However, there is no clear evidence that IP3 directly mediates an electrical response in OSNs, nor is there a clear rationale for two parallel excitatory odor transduction cascades. However, more recent data support the idea that phos-phoinositides or enzymes related to their metabolism may play a modulatory role, shaping the OSN output by... 

Fig. 5. Generation of the intracellular second messengers inositol 1,4,5-trisphosphate (iP3), 1,2-diacylglycerol (DAG) and Ca2+.

What are the biochemical effects of the second messenger inositol 1,4,5-trisphosphate These effects were delineated by microinjecting IP3 molecules into cells or by allowing IP3 molecules to diffuse into cells whose plasma membranes had... 

The active form of the G-protein, a-GTP, can modulate the activity of a true signal-generating enzyme or effector. For example (Fig. 21), a-GTP can activate the enzyme phosphatidylinositol-specific phospholipase C (PLC). PLC acts to break down the membrane phospholipid phos-phatidylinositol-4,5-bisphosphate (PIP2) to form two second messengers inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DG). IP3 diffuses into the cytoplasm, where it binds to an intracellular receptor and causes... 

Figure 2. The so-called canonical phosphoinositide pathway . The continuous phosphorylation/dephosphorylation reactions allow a steady-state level of Ptdins, PtdIns(4)P and PtdIns(4,5)P2 in the plasma membrane (PM). Cleavage of PtdIns(4,5)P2 by phospholipase C (PLC) generates the two well-known second messengers, inositol 1,4,5-trisphosphate (Ins(l,4,5)P3) and diacylglycerol (DAG). Besides its role as a protein kinase C (PKC) activator, DAG can be phosphorylated to phosphatidic acid (PA). The resynthesis of Ptdins from inositol and PA occurs mainly in the endoplasmic reticulum (ER). PPi, inorganic phosphate. PA-Pase, phosphatidic acid phosphatase. PA-TP, phosphatidic acid transport protein. PtdIns-TP, phosphatidylinositol transport protein. CDP-DAG, cytidine diphosphate-diacylglycerol. CMP, CDP and CTP, cytidine mono-, di- and triphosphate, respectively.

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 inositol is present in ph osphatidylinositol as the stereoisomer, myoinositol (Figure 14—8). Phosphatidylinositol 4,5-hisphosphate is an important constituent of cell membrane phosphohpids upon stimulation by a suitable hormone agonist, it is cleaved into diacylglycerol and inositol trisphosphate, both of which act as internal signals or second messengers. 

The other activity associated with transmembrane receptors is phospholipase C. Phosphatidyl inositol is a membrane phospholipid that after phosphorylation on the head group is found in the membrane as a phos-photidylinostitol bis phosphate. Phospholipase C cleaves this into a membrane associated diacylglycerol (the lipid part) and inositol trisphosphate (IP3, the soluble part). Both play a later role in elevating the level of the second messenger, Ca2+. 

D-myo-inositol 1,4,5 trisphosphate (I(1,4,5)P3) is a second messenger that liberates Ca2+ from the endoplasmic reticulum via intracellular... 

---