Second messengers inositol triphosphate

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

The intracellular hgand-gated Ca " channels include the channels in endoplasmic and sarcoplasmic reticulum (SR) membranes that are opened upon binding of the second messenger, inositol triphosphate (IP3). These are intracellular Ca release channels that allow Ca to exit from intracellular stores, and consequently to increase the concentration of cytoplasmic Ca [5]. A second type of intracellular Ca release channel is the Ca - and ryanodine-sensitive channel that was originally characterized and isolated from cardiac and skeletal muscle [5-7] but appears to exist in many types of cells. It has become evident that IP3-gated channels and ryanodine-sensitive channels are structurally related but distinct proteins [8] that are present in many cell types [9]. While very interesting, time and space will not allow for further discussion of these channels. 

Other receptor systems are coupled via GTP-binding proteins (G ), which activate phospholipase C. Activation of this enzyme releases the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG) from the membrane phospholipid phosphatidylinositol bisphosphate (P1P2). The IP3 induces release of Ca2+ from the sarcoplasmic reticulum (SR), which, together with DAG, activates protein kinase C. The protein kinase C serves then to phosphorylate a set of tissue-specific substrate enzymes, usually not phosphorylated by protein kinase A, and thereby affects their activity. 

FIGURE 2.7 Production of second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) through activation of the enzyme phospholipase C. This enzyme is activated by the a- subunit of Gq-protein and also by Py subunits of Gj-protein. IP3 stimulates the release of Ca2+ from intracellular stores while DAG is a potent activator of protein kinase C. 

PLC is a generic name for a family of isoforms of an enzyme which remain membrane bound as the presence of phospholipids is required for activity. Signal transduction via PLC as the effector is mediated by not one but two second messengers inositol 1,4,5 triphosphate (IP3) and DAG, which are the products of hydrolysis of membrane phospholipid by PLC (Figure 4.18). 

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.

Second messenger, these are molecules produced by cellular effectors that go on to activate other biochemical processes in the cell. Some examples of second messengers are cyclic AMP, inositol triphosphate, arachidonic acid, and calcium ion (see Chapter 2.2). 

Another type of NR crosstalk, which has only recently been recognized, is the so-called nongenomic actions of several receptors that induce very rapid cellular effects. Effectively, evidence has accumulated over several decades that steroid receptors may have a role that does not require their transcriptional activation, such as modifying the activity of enzymes and ion channels. While the effects of steroids that are mediated by the modulation of gene expression do occur with a time lag of hours, steroids can induce an increase in several second messengers such as inositol triphosphate, cAMP, Ca2+, and the activation of MARK and PI3 kinase within seconds or minutes. Many mechanistic details of these nongenomic phenomena remain poorly understood. Notably, controversy still exists as to the identity of the receptors that initiate the non-genomic steroid actions. However, it now appears that at least some of the reported effects can be attributed to the same steroid receptors that are known as NRs. 

Berridge, M.J. (1984). Inositol triphosphate and diacylglycerol as second messengers. Biochem. J. 220, 345-360. 

The intracellular processes which precede membrane activation appear to differ from those of MOE neurones, in that cyclic nucleotide gating may not occur. The transduction process which induces current flow in snake VN neurones, utilises as a putative second-messenger the modulator compound inositol triphosphate — Ins. (1,4,5) P3 = IP3 (Liu et al, 1999 Taniguichi et al, 2000). The proposed channel component associated with the microvillous membrane is one of the transient receptor potential family (TRPC-2 Heading Fig., pp. 94), the p-splice... 

Berridge M. J. Inositol triphosphate and diacy(glycerol TWo interacting second messengers. Annu Rev Biochem 1987 56, 159-93. 

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