Phosphodiesterase, retinal

Pertussis toxin is produced by the bacterium Bordetella pertussis. It covalently modifies G-proteins of the G/Go family (transfer of a ADP-ribose moiety of NAD onto G-protein a-subunits). ADP-ribosylated G-proteins are arrested in their inactive state and, as a consequence, functionally uncoupled from their respective effectors. Examples for pertussis toxin-sensitive cellular responses include the hormonal inhibition of adenylyl cyclases, stimulation ofK+ channels, inhibition of Ca2+ channels and stimulation ofthe cGMP-phosphodiesterase in retinal rods. 

Phosphodiesterase inhibitors should be used cautiously in patients at risk for retinitis pigmentosa and by pilots who rely on blue and green lights to land airplanes. Patients who experience sudden vision loss should be evaluated before continuing treatment. 

WARNING Renal impair is the major tox foUow administration instructions Uses CMV retinitis w/ HIV Action Selective inhibition of viral DNA synth Dose Rx 5 mg/kg IV over 1 h once/wk for 2 wk w/ probenecid Maint 5 mg/kg IV once/2 wk w/ probenecid (2 g PO 3 h prior to cidofovir, then 1 g PO at 2 h 8 h after cidofovir) X in renal impair Caution [C, -] Contra Probenecid or sulfa allergy Disp Inj SE Renal tox, chills, fever, HA, NA /D, thrombocytopenia, neutropenia Interactions t Nephrotox W/ aminoglycosides, amphot icin B, foscar-net, IV pentamidine, NSAIDs, vancomycin t effects W/zidovudine EMS Monitor ECG for hypocalcemia (t QT int val) and hypokalemia (flattened T waves) OD May cause renal failure hydration may be effective in reducing drug levels/effects Cilostazol (Pletal) TAntiplatelet, Arterial Vasodilator/ Phosphodiesterase Inhibitor] Uses Reduce Sxs of intermittent claudication Action Phosphodiesterase in inhibitor t s cAMP in pits blood vessels, vasodilation inhibit pit aggregation Dose 100 mg PO bid, 1/2 h before or 2 h after breakfast dinner Caution [C, +/-] Contra CHE, hemostatic disorders. 

Gtl/ Gt2 Photons (rhodopsin and color opsins in retinal rod and cone cells) t cGMP phosphodiesterase - cGMP (phototransduction)... 

Brown, R. L. (1992). Functional regions of the inhibitory subunit of retinal rod cGMP phosphodiesterase identified by site-specific mutagenesis and fluorescence spectroscopy. Biochemistry 31, 5918-5925. 

Otto-Bruc, A., Antonny, B., Vuong, T. M., Chardin, P., and Chabre, M. (1993). Interaction between the retinal cyclic GMP phosphodiesterase inhibitor and transducin. Kinetics and affinity studies. Biochemistry 32, 8636-8645. 

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. 

Fig. 2. Summary of regulatory GTPase cycle in photoactivation of cGMP-specific phosphodiesterase (PDE) in retinal rod cells. T, transducin (Gt) Rho, rhodopsin Rho, photoactivated Rho. PDE is represented as a heterotrimeric peripheral membrane protein, as is T. This regulatory cycle differs from that in Fig. 1 mainly in that the activation of PDE entails the dissociation of an inhibitory y subunit (PDEy) under the influence of activated Ta-GTP complex leading to formation of intermediary soluble Ta-GTP/PDEy complex. This complex persists until GTP is hydrolyzed to GDP, at which moment the inhibited PDEa/3y heterotrimer reforms. Dark adapted - non-activated - Rho is then required for reassociation of Ta-GDP to T/3y and release of GDP.

Three distinct G-proteins have been fully characterized. These are transducin (T), which allows rhodopsin to stimulate a high-affinity cyclic GMP phosphodiesterase upon photoactivation in retinal rods Gs, which allows receptors to stimulate the activity of adenylate cyclase and Gh which allows receptors to inhibit adenylate cyclase activity. These three G-proteins contain three non-identical subunits (a, /3 and y). It is their a subunits which provide the binding site for GTP as well as distinct sites for interaction with specific receptor and effector systems and for Mg2+. The /3 subunits associated with all three regulatory proteins are apparently identical although T has a different y subunit. 

Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase See comments. Nature 347 677-680. 

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