Second messengers synthesis

Interference with signal transduction by reducing second-messenger synthesis through. 

Variability in hormonal response patterns does not stop at the level of second-messenger synthesis. Thus, cyclic AMP can activate the well-known cAMP-dependent protein kinase A, but the possibility of other cAMP-respon-sive enzymes or cAMP-activated regulatory proteins should not be ruled out. The protein kinase activated by cAMP can activate a number of other enzymes. For example, in the liver, phosphorylase kinase (see fig. 24.15) is activated and catalyzes the breakdown of glycogen. In adipocytes, triacyl-glycerol lipase is activated and catalyzes the breakdown of triacylglycerols. 

J. Insulin second messengers synthesis of 6-0-(2-amino-2-deoxy-a-D-glucopyrano-sylJ-D-chiro-inositol-l-phosphate. Tetrahedron, Lett., 1993, 34, 7869-7872. 

The regulation of receptor synthesis is a second component of receptor downregulation. It involves processes that reduce gene transcription, mRNA stability, and receptor half-life time. It should be noted that mechanisms in addition to the regulation of the receptor number may account for tolerance development. Second messenger levels and enzyme activities that participate in the signaling of a given receptor are... 

Taking ai-adrenoceptors as an example, several possible mechanisms have been suggested (see Starke 1987). The first rests on evidence that these autoreceptors are coupled to a Gi (like) protein so that binding of an a2-adrenoceptor agonist to the receptor inhibits the activity of adenylyl cyclase. This leads to a fall in the synthesis of the second messenger, cAMP, which is known to be a vital factor in many processes involved in exocytosis. In this way, activation of presynaptic a2-adrenoceptors could well affect processes ranging from the docking of vesicles at the active zone to the actual release process itself... 

The exact process(es) by which a2-adrenoceptors blunt release of transmitter from the terminals is still controversial but a reduction in the synthesis of the second messenger, cAMP, contributes to this process. a2-Adrenoceptors are negatively coupled to adenylyl cyclase, through a Pertussis toxin-sensitive Gi-like protein, and so their activation will reduce the cAMP production which is vital for several stages of the chemical cascade that culminates in vesicular exocytosis (see Chapter 4). The reduction in cAMP also indirectly reduces Ca + influx into the terminal and increases K+ conductance, thereby reducing neuronal excitability (reviewed by Starke 1987). Whichever of these releasecontrolling processes predominates is uncertain but it is likely that their relative importance depends on the type (or location) of the neuron. 

Figure 7.1 Schematic of the prototypical dopaminergic synapse. Pre- and post-synaptic components of a dopaminergic synapse summarizing molecular pathways for dopamine synthesis, metabolism, and second messenger effects following Dl-like or D2-like receptor activation. (See also Plate 6.)...

Figure 9-7 Synthesis and Degradation of the Second Messenger, cAMP...

G-proteins are easy. The GTP-bound form can interact successively with several molecules of its target before the GTP is hydrolyzed and the G-protein is inactivated. The synthesis of cyclic nucleotide second messengers by the cyclase is also an obvious amplification step. 

Palfrey, H. C. and Nairn, A. C. Calcium-dependent regulation of protein synthesis. Adv. Second Messenger Phosphoprotein Res. 30 191-223,1995. 

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. 

Glycerophospholipids are used for membrane synthesis and for producing a hydrophilic surface layer on lipoproteins such as VLDL. In cell membranes, they also serve as a reservoir of second messengers such as diacylglycerol, inositol 1,4,5-triphosphate, and arachidonic acid. Their structure is similar to triglycerides, except that the last fatty acid is replaced by phosphate and a water-soluble group such as choline (phosphatidylcholine, lecithin) or inositol (phosphatidyl-inositol). 

Although details will vary, in each case an agonist at its receptor activates adenylate cyclase and the second messenger cAMP is produced from ATP. cAMP activates protein kinase A and a cascade of reactions may follow. These may be metabolic reactions, as in the cases just described, or activation of a cAMP response-element protein, CREB. CREB is a transcription factor with affinity for specific sites on DNA. Control of protein synthesis follows. 

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