The positive role of the carboxyl terminus of the gamma subunit of retinal cGMP-phosphodiesterase in maintaining phosphodiesterase activity in vivo.
The inhibitory rod cyclic GMP-phosphodiesterase gamma subunit, PDEgamma, is a key component of the photoresponse and is required to support rod integrity. Pdeg(tm1)/Pdeg(tm1) mice that lack PDEgamma due to a targeted disruption of the gene encoding PDEgamma, (Pdeg) suffer from a very rapid and severe photoreceptor degeneration. Previously, deletions in the carboxyl-terminal domain of PDEgamma blocked its ability to inhibit trypsin-activated PDE activity, in vitro. In other words, these mutations eliminated PDEgamma's control on the catalytic activity of PDEalpha and PDEbeta. To study the in vivo effects resulting from the deletion of the last seven amino acids of the PDEgamma carboxyl terminal, this PDEgamma allele (Del7C) was introduced as a transgene Pdeg(tm1)/Pdeg(tm1) mice. These animals could only synthesize transgenic mutant PDEgamma. The mutant retinas were expected to display a higher basal level of PDE activity and lower cGMP levels in light and darkness than the PDEgamma knockout mice, which would allow the rescue of their photoreceptors. Instead, our results showed that the Del7C transgene could not complement the Pdeg(tm1)/Pdeg(tm1) mutant for photoreceptor survival. In fact, animals carrying the Del7C transgene have low PDE activity as well as reduced PDEalpha and PDEbeta content.
Tsang
Stephen H
SH
Jules Stein Eye Institute, UCLA School of Medicine, 100 Stein Plaza, Los Angeles, CA 90095-7000, USA.
Yamashita
Clyde K
CK
Lee
Won Ho
WH
Lin
Chyuan Sheng
CS
Goff
Stephen P
SP
Gouras
Peter
P
Farber
Debora B
DB
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000235:genetics*; D000818:Animals; D004596:Electroretinography; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012160:Retina / Q000201:enzymology* / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000201:enzymology / Q000503:physiopathology*; D020079:Terminal Repeat Sequences
D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases