Phosphodiesterases transduction

FIGURE 50-5 A model for the transduction of odors in OSNs. The individual steps are detailed in the text. Note that several feedback loops modulate the odor response, including inhibition of the CNG channel by Ca2+ ions (purple balls) that permeate the channel, and a Ca2+/calmodulin (CaM) -mediated desensitization of the channel that underlies rapid odor adaptation. Several other mechanisms, including phosphodiesterase-mediated hydrolysis of the second messenger, cAMP, and phosphorylation of the OR by various kinases, have also been described. 

Many bixxer compounds contain both hydrophobic and hydrophilic sites which can alter cell membranes through penetration. There is a correlation between bitter intensity and hydrophobicity-solubility indexes such as fee octanol/water partition coefficient, lo (7). Penetration may directly affect cAMP phosphodiesterase as part of fee transduction process (see below). A bitter receptor protein may be involved wife certain bitters, such as specific structural requirements wife fee bitter tasting dipeptides and denatonium salts (27). The latter is used in some consumer products to avoid accidental ingestion. A receptor mechanism is also supported by fee existence of a genetic "taste blindness" for some bitter materials (see below). 

Fig. 7.6. Feedback control of protein kinase A by a phosphodiesterase. On activation of protein kinase A, the catalytic C subnnits are released, which then phosphorylate a phosphodiesterase, in addition to other substrates. The phosphodiesterase is activated by the phosphorylation and hydrolyzes cAMP to AMP, whereby the signal transduction via protein kinase A is reduced or terminated.

The effect of FTIs on retinal function also needs to be carefully examined. Several proteins involved in retinal signal transduction are farnesylated in vivo, presumably by FTase. These include rod cell cGMP phosphodiesterase a-subunit,108,109 rod cell transducin y-subunit,110,111 and rhodopsin kinase.112 Since the retina consists of terminally differentiated, nondividing cells, the anti-proliferative properties of FTIs should be inconsequential. Visual function could possibly be affected by alterations in the prenylation of proteins involved in retinal signal transduction, although any changes of this sort should be reversible. 

In general, the MC2 receptor is Gs protein-coupled (Table 1), and two studies in the rabbit pulmonary artery indicate that this is also true for the presynaptic receptor. The evidence is, indirect, however, in that it suggests activation of adenylyl cyclase, the typical transduction step downstream from Gs. In the study by Gothert and Hentrich (1984), the facilitatory effect of ACTH was increased by simultaneous administration of forskolin, an activator of the catalytic subunit of adenylyl cyclase, and AH 21-132, a phosphodiesterase inhibitor. In the study by Costa and Majewski (1988), the facilitatory effect of ACTH was occluded when the vessel was super-fused with a lipid-soluble cAMP analogue. 

Juilfs D. M., Fiille H.-J., Zhao A. Z., Houslay M. D., Garbers D. L. and Beavo J. A. (1997) A subset of olfactory neurons that selectively express cGMP-stimulated phosphodiesterase (PDE2) and guanylyl cyclase-D define a unique olfactory signal transduction pathway. Proc. Natl. Acad. Sci. USA 94, 3388-3395. 

FIGURE 11.2 Interactions of vanadium with the hormone-sensitive G protein modulated cAMP producing signal transduction system. Bold lines with arrows leading away from V represent stimulation, blunt-ended lines represent inhibition. V shows where vanadium interactions have geen found. Pase phosphatase, PDE(IV) phosphodiesterase (IV), PEPCK phosphoenolpyrurate carboxykinase, PKA, protein kinse A inactive, PKAa PKA active. This figure was adapted from [13]. 

G-protein-controlled phosphodiesterase may be involved in signal transduction [55], but the exact localization remains to be established. 

---