AMP pathways

Upregulation of the cyclic AMP pathway is one mechanism underlying opiate addiction 411... 

Upregulation of the cyclic AMP pathway is one mechanism underlying opiate addiction. The mechanisms by which opiates induce tolerance, dependence and withdrawal in specific target neurons has been a major focus of research for many years. The inability to account for prominent aspects of opiate addiction solely on the basis of alterations in endogenous opioid peptides or in opiate receptors has shifted attention to postreceptor mechanisms [66]. 

Suzuki T, Ise Y, Tsuda M, Maeda J, Misawa M (1996) Mecamylamine-precipitated nicotine-withdrawal aversion in rats, Eur J Pharmacol 314 281-284 Suzuki T, Ise Y, Mori T, Misawa M (1997) Attenuation of mecamylamine-precipitated nicotine-withdrawal aversion by the 5-HT3 receptor antagonist ondansetron. Life Sci 6LPL249-254 Tzavara ET, Monory K, Hanoune J, Nomikos GG (2002) Nicotine withdrawal syndrome behavioural distress and selective up-regulation of the cyclic AMP pathway in the amygdala. Eur J Neurosci 16 149-153... 

Stanhill A, Schick N, Engelberg D, The Yeast Ras/Cyclic AMP pathway induces invasive growth by suppressing the cellular stress response, Mol Cell Biol 19 64— 67, 1999. 

In the calyx of Held synapse in the auditory brainstem of rats the 5-HTib receptor inhibition of glutamate release was fully explained by inhibition of Ca2+ entry through voltage-dependent channels (Mizutani et al. 2006). In rat nucleus accumbens, in contrast, the analogous 5-HTib effect did not involve inhibition of Ca2+ channels (Muramatsu et al. 1998). In rat amygdala, the 5-HTia inhibition operated via a cyclic AMP pathway and apparently inhibition of Ca2+ entry an unexplained observation was the failure of pertussis toxin to abolish the 5-HTia inhibition (Cheng et al. 1998). 

REGULATION OF THE AMP PATHWAY. HEAVY WHITE ARROWS INDICATE COMPOUNDS THAT SLOW DOWN SYNTHESIS HEAVY BLACK ARROWS INDICATE COMPOUNDS THAT SPEED UP SYNTHESIS. 

No one has a clue how the AMP pathway developed. Although a few researchers have observed that the pathway itself presents a severe challenge to gradualism, no one has written about the obstacle posed by the need to regulate a cell s metabolic pathway immediately at its inception. Small wonder—no one wants to write about road kill. 

Matsuura, A., and Anraku, Y. (1993). Characterization of the MKSl gene, a new negative regulator of the ras-cyclic AMP pathway in Saccharomyces cemuisiae. Mol Gen. Genet. 238, 6. 

HT receptors occur on neurons within the inferior and superior colliculi and in the hippocampus. Activation of5-HT receptors stirmilates the G -adenylyl cyclase-cyclic AMP pathway. 

The actions of LH and hCG are mediated by the LH receptor, while those of FSH are mediated by the FSH receptor. These receptors couple to G, to activate the adenylyl cyclase-cyclic AMP pathway and most, if not aU, of the actions of the gonadotropins can be mimicked by cyclic AMP analogs. 

Some of the steroid-oxidizing P450s are regulated by adrenocorticotropic hormone (ACTH) and cyclic adenosine monophosphate (AMP) pathways [181],... 

By analogy with other transmembrane signaling systems—the cyclic AMP pathway for instance—one would expect the arachidonic acid cascade to be regulated both positively, as we have summarized above, and negatively. While evidence for an inhibitory control has been obtained, it is admittedly still very incomplete. In fact, to the best of my knowledge, only two examples of such control have been reported. 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Draw the structure of adenosine 5 -monophosphate (AMP), an intermediate in some biochemical pathways. 

FIGURE 2.6 Production of cyclic AMP from ATP by the enzyme adenylate cyclase. Cyclic AMP is a ubiquitous second messenger in cells activating numerous cellular pathways. The adenylate cyclase is activated by the a subunit of Gs-protein and inhibited by the a-subunit of Gj-protein. Cyclic AMP is degraded by phosphodiesterases in the cell. 

The metabolic control is exercised on certain key regulatory enzymes of a pathway called allosteric enzymes. These are enzymes whose catalytic activity is modulated through non-covalent binding of a specific metabolite at a site on the protein other than the catalytic site. Such enzymes may be allosterically inhibited by ATP or allosterically activated by ATP (some by ADP and/or AMP). 

The tethering of PKA through AKAPs by itself is not sufficient to compartmentalize and control a cAMP/ PKA-dependent pathway. Cyclic AMP readily diffuses throughout the cell. Therefore, discrete cAMP/PKA signalling compartments are only conceivable if this diffusion is limited. Phosphodiesterases (PDE) establish gradients of cAMP by local hydrolysis of the... 

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