Adenosine transduction

Calculation of Conformational Free Energies for a Model of a Bilobal Enzyme Protein kinases catalyze the transfer of phosphate from adenosine triphosphate (ATP) to protein substrates and are regulatory elements of most known pathways of signal transduction. 

Dl-iike receptors activate the Gs transduction pathway, stimulating the production of adenylyl cyclase, which increases the formation of cyclic adenosine monophosphate (cAMP) and ultimately increases the activity of cAMP-dependent protein kinase (PKA). PKA activates DARPP-32 (dopamine and cyclic adenosine 3, 5 -monophosphate-regulated phosphoprotein, 32 kDa) via phosphorylation, permitting phospho-DARPP-32 to then inhibit protein phosphatase-1 (PP-1). The downstream effect of decreased PP-1 activity is an increase in the phosphorylation states of assorted downstream effector proteins regulating neurotransmitter... 

FIGURE 14-6 Main signaling pathways for histamine receptors. Histamine can couple to a variety of G-protein-linked signal transduction pathways via its four different receptors. The Hj receptor activates the phosphatidylinositol turnover via Gq/11 proteins. The other receptors either positively (H2 receptor) or negatively (H3 and H4 receptor) regulate adenylyl cyclase activity via Gs and GUo protein activation respectively. Several additional signaling pathways have been described, which are not shown. Abbreviations PfP2, phosphatidylinositol 4,5-bisphosphate PIC, phospholipase C AC, adenylyl cyclase ATP, adenosine triphosphate cAMP, cyclic AMP PKC, protein kinase C PICA, protein kinase A. 

Sulfation in most aspects is very similar to phosphorylation, except that sulfation is not involved in intracellular signal transduction, but in other forms of signaling. The mechanism of sulfation is similar to that of phosphorylation as a general base from the enzyme active site that deprotonates the hydroxyl groups of tyrosine residues. The nucleophilic oxygen then attacks the /3-position, in contrast to the 7-position in phosphorylation, and releases adenosine 3, 5 -diphosphate. 

Studies of peripheral NE receptor function have also shown alterations in a2 receptor and cyclic adenosine 39,59-monophosphate (cAMP) function in patients with PTSD. Decreases in platelet adrenergic a2-receptor number (Perry et al. 1987), platelet basal adenosine, isoproterenol, forskohn-stimulated cAMP signal transduction (Lerer et al. 1987), and basal platelet monoamine oxidase (MAO) activity (Davidson et al. 1985) have been found in PTSD. These findings may reflect chronic high levels of NE release which lead to compensatory receptor down-regulation and decreased responsiveness. 

Fishman P, Bar-Yehuda S, Madi L, Rath-Wolfson L, Ochaion A, Cohen S, Baharav E (2006) The PI3K-NF-kappaB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis. Arthritis Res Ther 8(1) R33 Fossetta J, Jackson J, Deno G, Fan X, Du XK, Bober L, Soude-Bermejo A, de Bouteiller O, Caux C, Lunn C, Lundell D, Palmer RK (2003) Pharmacological analysis of calcium responses mediated by the human A3 adenosine receptor in monocyte-derived dendritic cells and recombinant cells. Mol Pharmacol 63(2) 342-350... 

Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, Barer F, Zabutti A, Perez-Liz G, Del Valle L, Fishman P (2008) The A, adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways. Int J Oncol 33(2) 287-295... 

H3 receptor activation attenuates the release of glutmate in several brain regions (Table 3), but an endogenous input to the receptors has not been demonstrated. In the dentate gyrus adenosine, acting at Ai receptors, also attenuated the release of glutamate and occluded further inhibition by histamine, presumably because a common signal transduction pathway (Brown and Haas 1999). 

Figure 1 summarizes the different transduction mechanisms. Interestingly, adenylate cyclase, a common target of Gi/0 proteins in other biological systems, does not seem to be involved in the intracellular effects triggered by activation of presynaptic Ai adenosine receptors (Fredholm et al. 1986 Fredholm and Lindgren 1987). 

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