Second messenger systems

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

There are numerous second messenger systems such as those utilizing cyclic AMP and cyclic GMP, calcium and calmodulin, phosphoinosiddes, and diacylglerol with accompanying modulatory mechanisms. Each receptor is coupled to these in a variety of ways in different cell types. Therefore, it can be seen that it is impractical to attempt to quantitatively define each stimulus-response mechanism for each receptor system. Fortunately, this is not an... 

Screening. See High-throughput screening Second messenger systems calcium ion, 83 description of, 24 production of, 25f Series hyperbolae, 38 Serotonin, 150, 151 f Seven transmembrane receptors, 3-4 Shennong Herbal, 147 Short interfering RNA duplex molecules, 184... 

Calmodulin and cyclic nucleotide-dependent second messenger systems... 

Fig, 2. Regulation of L-type channels by multiple second messenger systems. The cartoon is based on what is known or speculated about how L-type Ca channels might be regulated by proeesses that involve phosphorylation by different receptor mediated pathways. The actual receptors and number of pathways may vary in different cell types. The cartoon is loosely based on events that might occur in a cardiac cell. 

Mechanism of Action Lithium s pharmacologic mechanism of action is not well understood and probably involves multiple effects. Possibilities include altered ion transport, increased intraneuronal catecholamine metabolism, neuroprotection or increased brain-derived neurotrophic factor, inhibition of second messenger systems, and reprogramming of gene expression.29... 

Furthermore, each class has at least two subtypes of receptors alr a2, Plr and P2- All of these receptors are linked to G proteins and second messenger systems that carry out the intracellular effects. 

As with signal transduction and second messenger systems, the mechanism of gene activation allows for amplification of the hormone s effect. 

G protein Receptor subtype Second messenger system... 

Childers SR. Opioid receptor-coupled second messenger systems. Life Sci 1991 48 1991. 

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action. Hormones act either via cell-surface or intracellular receptors. Peptide hormones and amino-acid derivatives, such as epinephrine, act on cell-surface receptors that do such things as open ion-channels, cause rapid electrical responses and facilitate exocytosis of hormones or neurotransmitters. Alternatively, they activate second-messenger systems at the cell membrane, such as those involving cAMP, Ca2+/ calmodulin or phosphoinositides (see Chs 20 and 24), which leads to phosphorylation of proteins inside various parts of the target cell (Fig. 52-2A). Steroid hormones and thyroid hormone, on the other hand, act on intracellular receptors in cell nuclei to regulate gene expression and protein synthesis (Fig. 52-2B). Steroid hormones can also affect cell-surface events via receptors at or near the cell surface. 

As we have noted, second-messenger systems, through phosphorylation of nuclear proteins, can influence gene expression. There is evidence that even the classical steroid... 

FIGURE 52-2 There are two modes of hormonal action. (A) Activation of cell-surface receptors and coupled second-messenger systems, with a variety of intracellular consequences. (B) Entry of hormone into the target cell, binding to and activation of an intracellular receptor and binding of the receptor-hormone complex to specific DNA sequences to activate or repress gene expression. DAG, diacylglycerol HRE, hormone-response element. 

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