Hormone or neurotransmitter signaling is mediated by transient fluctuations in intracellular cAMP within a very narrow range of concentrations (1). Maximal biological effects are elicited with only 2-3-fold changes in intracellular cAMP levels, while the cell potential for cAMP production is usually much larger. In addition, the increase in intracellular cAMP is transient despite the continuous presence of the extracellular stimulus (2, 3). This limited and short-lived nature of the activating signal is an essential feature of hormone or neurotransmitter action. This is necessary to decrease the intrinsic "noise" in the signaling mechanism, to allow iterative signaling, and to prevent excessive stimulation.The rapid and transient changes in cAMP concentrations are the result of changes in both synthesis and degradation of the second messenger cAMP, involving steps at the receptor as well as at a postreceptor level (4, 5). Following the activation of G s and adenylyl cyclase, receptor phosphorylation causes an uncoupling from G s , and therefore a decrease in cAMP synthesis. For the ␤ 2 -adrenergic receptor, ␤ 2 -adrenergic receptor kinases phosphorylate only agonist-occupied active receptors and enhance the affinity of the receptors for the inhibitor protein ␤-arrestin (6). Binding of ␤-arrestin to the phosphorylated receptors inhibits the receptor-G s interaction, thereby inducing the uncoupled or desensitized state of the receptors (7). Several kinases have also been implicated in the phosphorylation of the glycoprotein receptors including the GRK kinases, PKA 1 and PKC. While PKA efficiently phosphorylates and uncouples the ␤-adrenergic receptor (5), the involvement of this kinase in the glycoprotein receptor phosphorylation is less clear (8).In addition to receptor uncoupling from G protein and cyclase, rapid modulation of phosphodiesterases and of cAMP degradation plays an essential role in the transient accumulation of cyclic nucleotides (9). This concept was initially inferred by the use of xanthine inhibitors of PDEs and by measuring the decay of the cAMP signal in intact cells (3). The use of cAMP analogs has confirmed that cAMP-dependent PKA activation in the cell causes an activation of cAMP degradation (10 -12). The impact and physiological significance of this rapid feedback regulation is unclear.Of the many PDEs expressed in the cell, two isoforms are activated by an increase in cAMP. In platelets (13,14) and adipocytes (15, 16) a type 3 PDE is activated by a PKA-dependent phosphorylation lowering cAMP levels. Recently, a distinct PDE isoenzyme, a member of the PDE4 family, has been implicated in this feedback regulation (17). In thyroid cells, TSH causes a PKA-mediated phosphorylation and activation of a PDE4D3 variant. This conclusion is supported by studies involving PDE4-specific inhibitors and immunoprecipitation with PDE4-selective antibodies (17), and is consistent with cell-free phosphorylation and activation of the recombinant PDE4D3 enzymes (18). The site of PKA phosphorylation of PDE4D3 ...

The effects of dietary restriction of a single essential amino acid (EAA) on insulin-like growth factor-I (IGF-I) and IGF-binding protein (IGFBP)-1 were investigated in rats. Rats were fed experimental diets containing amino acid (AA) mixtures in which the concentrations of all EAA were at levels recommended by the National Research Council (control), in which a single EAA was restricted to 20% of that of the control diets (Leu(-), Lys(-), Met(-) or Thr(-)), or in which the diet was devoid of amino acids (AA(-)). To eliminate the effect of differences in energy intake, rats were fed the mean amount of food as consumed by the AA(-) group on the previous day. Growth was significantly retarded in rats fed diets restricted in just one EAA compared with that of rats fed the control diet, and further growth retardation was observed in rats fed the AA(-) diet. On the other hand, the plasma IGF-I concentrations in the groups with a single EAA restriction or in the AA(-) group were 66% (P: < 0. 05) and 50% (P: < 0.05) of that of the control group, respectively. The effect of any single EAA restriction was not significantly different from that of total AA deprivation. The plasma IGFBP-1 concentration in the control group did not differ from that of rats fed diets with the single EAA restrictions except for methionine restriction, but it was approximately 6-fold greater in the AA(-) group. Differences in plasma IGFBP-1 concentration under these conditions could be explained by differences in hepatic IGFBP-1 mRNA contents. Based on these results, we conclude that restriction of single EAA does not affect IGFBP-1 synthesis in vivo, although the deprivation of a single EAA has been reported to increase IGFBP-1 production in hepatocyte cultures. Our results also indicated that a single EAA restriction decreased IGF-I production but did not affect IGFBP-1 production. The present study suggests that not only plasma IGF-I, but also IGFBP-1, affects the magnitude of growth retardation in vivo.