Second messengers precursors

Interest in the PGs has recently reverted to their precursor arachidonic acid (AA), which seems to be able to act intracellulary as a second messenger, and also extra-cellularly. In this latter mode it may play a part in LTP. It is known that AA produces a long-lasting enhancement of synaptic transmission in the hippocampus that resembles LTP and in fact activation of NMDA receptors leads to the release of AA by phospholipase A2 (see Dumuis et al. 1988) and inhibition of this enzyme prevents the induction of LTP. AA has also been shown to block the uptake of glutamate (see Williams and Bliss 1989) which would potentiate its effects on NMDA receptors. This would not only prolong LTP but also cause neurotoxicity. 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Inositol lipids can serve as mediators of other cell functions, independent of their role as precursors of second messengers 358... 

In summary, IL-1 and TNF-a activate mature osteoclasts indirectly via a primary effect on osteoblasts and by inhibiting osteoclast apoptosis. In addition, they increase osteoclast formation either by directly stimulating the proliferation of osteoclast precursors or by increasing the pro-osteoclastogenic capacity of bone stromal cells. Although in vitro TNF-a and IL-1 can apparently induce the development of TRAP+ osteoclasts in the absence of RANKL/RANK, all data seem to indicate that TNF-a and IL-1 potentiate osteoclast development via the activation of common second messenger systems, such as NF-/cB activation, and that the effects on OCS require the RANKL/RANK system (Jones et al. 2002). 

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). 

Phosphatidylinositol-4,5-Bisphosphate, a Precursor of Second Messengers, Is Synthesized via CDP-Diacylglycerol... 

Fatty acids are components of a rich variety of complex lipid molecules that play critical structural roles in membranes. Some of these lipids are also the precursors of compounds with hormone or second-messenger activities. In this chapter we focused on the metabolism of these compounds with some mention of their functions. The following points are the highlights of our discussion. 

IP3 is classified now as a second messenger with considerable influence on calcium movement from intracellular stores in a cell. Furthermore, diglycerides have a considerable and important effect on protein kinase C activity and location (Nishizuka, 1992). This is a classic example of an inactive (precursor) molecule being converted to a biologically active product. This reaction is an excellent example of the role of phospholipids in membrane processes through an enzyme-catalyzed reaction. 

The nicotinamide nucleotide coenzymes function as electron carriers in a wide variety of redox reactions. In addition, NAD is the precursor of adenine dinucleotide phosphate (ADP)-ribose for ADP-ribosylation and poly(ADP-ribosylation) of proteins and cADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). They act as second messengers and stimulate increases in intracellular calcium concentrations. 

NAD is the source of ADP-ribose for the modification of proteins by mono-ADP-ribosylation, catalyzed by ADP-ribosyltransferases (Section 8.4.2), and poly(ADP-ribosylation), catalyzed by poly(ADP-ribose) polymerase (Section 8.4.3). It is also the precursor of two second messengers that act to increase the intracellular concentration of calcium, cADP-ribose, and nicotinic acid adenine dinucleotide phosphate (Section 8.4.4). 

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