Second messenger pathways

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. 

By interfering with any one of the many phases associated with these second messenger pathways, toxins may alter channel gating. For example, the blue green algal toxins, aplysiatoxin, and lyngbyatoxin bind to and activate protein kinase C in a manner similar to phorbol esters (73). They also stimulate arachidonic acid metabolism (74). The coral toxin, palytoxin, also stimulates arachidonic acid breakdown albeit by an unknown mechanism (74) and affects other biochemical activities of the cell (see chapters by Fujiki et al., Wattenberg et al., and Levine et al., this volume). 

Gopalakrishnan, M., Molinari, E., Sullivan, J. Regulation of human 0 ,P2 neuronal nicotinic acetylcholine receptors by cholinergic channel ligands and second messenger pathways. Mol. Pharmacol. 52 524, 1997. 

Currently, three subtypes of histamine receptors are proposed and H2 receptors are found in peripheral tissues and the central nervous system (CNS), and receptors are found in the CNS. The second messenger pathway that mediates Hrreceptor stimulation is... 

Multiple interactions are also being demonstrated between the traditional second-messenger pathways and the MAPK cascades. Free (3y G protein subunits, generated upon activation of receptors coupled to the G family, lead to activation of the ERK pathway. The mechanism by which this occurs, which may involve an interaction between the subunits and Ras or Raf, is a subject of intensive research (see Ch. 19). In addition, increases in cellular Ca2+ concentrations lead to stimulation of the ERK pathway, apparently via phosphorylation by CaMKs of proteins, for example She and Grb, that link growth factor receptor tyrosine kinases to Ras. Activation of the... 

Odorant recognition initiates a second-messenger cascade leading to the depolarization of the neuron and the generation of action potentials 821 Negative-feedback processes mediate adaptation of the olfactory transduction apparatus to prolonged or repetitive stimulation 823 Alternative second-messenger pathways maybe at work in olfactory transduction 823... 

Sweet, bitter and umami taste involve receptor-coupled second-messenger pathways that are differentially expressed across the gustatory epithelium 827... 

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... 

Upregulation of the cAMP second-messenger pathway is a well-established molecular adaptation 916... 

Mouradian, R.D., Seller, F.M., and Waterhouse, B.D. (1991) Noradrenergic potentiation of excitatory transmitter action in cerebro-cortical slices evidence of mediation by an alphaj-receptor-linked second messenger pathway. Brain Res 546 83-95. 

The cAMP second messenger pathway. Key proteins include hormone receptors (Rec), a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits,... 

Figure 2 Known second-messenger pathways that modulate capsaicin or VRs. GPCR, G protein-coupled receptors PLA2, phospholipase A2 AC, adenylate cyclase IP3, inositoltriphosphate DAC diacylglycerol LM, lipoxygenase metabolites AA, arachidonic acid ANA, anandamide PG, prostaglandins Gq/11, Gq/j, Gs, trimeric G-proteins (adapted from Premkumar, 2001)...

Adenosine A3 receptors have been shown to couple to classical or G protein-dependent second-messenger pathways through activation of both Gi family and Gq family G proteins (Palmer et al. 1995 Merighi et al. 2003 Hasko and Cronstein 2004). 

The entry of calcium into neurons via presynaptic calcium channels is a key step in evoked neurotransmitter release. Compromised calcium channel function can lead to severe neurological consequences, and yet the pharmacological inhibition of specific calcium channel subtypes can be beneficial in the treatment of conditions such as neuropathic pain. Because of the importance of these channels, neurons have evolved complex means for regulating calcium channel activity, including activation of second messenger pathways by G protein coupled receptors and feedback inhibition by calcium binding proteins. By these means, neurons are able to maintain the fine balance of cytoplasmic calcium levels that is required for optimal neurotransmitter release. 

Boekhoff, I., Michel, W. C., Breer, H., and Ache, B. W., Single odors differentially stimulate dual second messenger pathways in lobster olfactory cells, J. Neurosci., 14, 3304, 1994. 

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