Second messenger, transport

Group II assays consist of those monitoring cellular second messengers. Thus, activation of receptors to cause Gs-protein activation of adenylate cyclase will lead to elevation of cytosolic or extracellularly secreted cyclic AMP. This second messenger phosphorylates numerous cyclic AMP-dependent protein kinases, which go on to phosphorylate metabolic enzymes and transport and regulatory proteins (see Chapter 2). Cyclic AMP can be detected either radiometrically or with fluorescent probe technology. 

Family of enzymes phosphorylating phosphatidylinositol (Ptdlns), PtdIns(4)phosphate, and PtdIns(4,5)phosphate in the 3-position. The Ptdlns(3 phospholipids are second messengers in processes like cell growth, cytoskeletal rearrangement, and vesicular transport. PI 3-kinases are heterodimers composed of a catalytic and a regulatory subunit. The enzymes are activated by insulin, many growth factors, and by a variety of cytokines. Their activity can be inhibited by wortmannin and LY294002. 

Bonisch, H, Hammermann, R and Bruss, M (1998) Role of protein kinase C and second messengers in regulation of the norepinephrine transporter. Adv. Pharmacol. 42 183-186. 

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... 

Lead also has been shown to substitute for calcium in the activation of calmodulin, but this requires higher levels of lead than does the activation of protein kinase C. Nevertheless, the affinity of lead for calmodulin is higher than that of calcium. Once activated, calmodulin regulates the activity of certain enzymes and transporters. For example, it activates c-AMP phosphodiesterase to hydrolyze and terminate the action of cAMP, another second messenger (Bressler and Goldstein 1991 Goldstein 1993 Goering 1993). 

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. 

Eukaryotic ABC transport system Phosphotransferase system (PTS) Ion-coupled transport system Signal Transduction Two-component system Bacterial chemotaxis MAPK signaling pathway Second messenger signaling pathway Ligand-Receptor Interaction G-protein-coupled receptors Ion-channel-linked receptors Cytokine receptors Molecular Assembly Ribosome assembly Flagellar assembly Enzyme assembly... 

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]. 

Lithium carbonate and lithium citrate are the most commonly used compounds. Lithium has effects on cation transport, on individual neurotransmitters (including 5-HT) and on intracellular second messenger systems. Which of these is key to its therapeutic efficacy is not entirely clear but, as for the antidepressant drugs, the net effects seem to be to enhance serotonin function and to stabilise the noradrenergic system. Once lithium treatment is established it is very important that it is not suddenly stopped as this may result in rebound hypomania. 

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