Retinal cGMP phosphodiesterase

Polypeptides that have these C-terminal modifications include the ras proto-oncogene proteins and many of their small G-protein analogs, the y-subunits of the large G-proteins, and the retinal cGMP phosphodiesterase (Clarke, 1992). These proteins are all involved in the transduction of information from the exterior environment of a cell to its interior. The modification of these proteins can allow for specific interactions with the membrane bilayer or with specific receptor proteins on the plasma membrane or internal membrane systems. The specific role of the C-terminal methylation reaction has been tested recently in the yeast system. 

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. 

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. 

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. 

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. 

Pfister C, Bennett N, Bruckert F, Catty P, Clerc A, Pages F, Deterre P (1993) Interactions of a G-protein with its effector transducin and cGMP phosphodiesterase in retinal rods. Cell Signal 5 235-241 Pick E, Keisari Y (1980) A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J Immunol Methods 38 161-170... 

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.

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