Phosphorylation by cyclin-dependent protein kinase 5 of the regulatory subunit (Pgamma) of retinal cgmp phosphodiesterase (PDE6): its implications in phototransduction.
Cyclic GMP phosphodiesterase (PDE6) is a key enzyme in vertebrate retinal phototransduction. After GTP/GDP exchange on the a subunit of transducin (Talpha) by illuminated rhodopsin, the GTP-bound form Talpha (GTP/Talpha) interacts with the regulatory subunit (Pgamma) of PDE6 to activate cGMP hydrolytic activity. The regulatory mechanism of PDE6 has been believed to be a typical G protein-mediated signal transduction process. We found that cyclin-dependent protein kinase 5 (Cdk5) phosphorylates Pgamma complexed with GTP/Talpha in vitro and in vivo. Phosphorylated Py dissociates from GTP/Talpha without GTP hydrolysis and interacts effectively with catalytic subunits of PDE6 to inhibit the enzyme activity. These observations provide new twists to the current model of retinal phototransduction. In this article, in addition to the details of Py phosphorylation by Cdk5, we review previous studies implying the Pgamma phosphorylation and the turnoff of PDE6 without GTP hydrolysis and indicate the direction for future studies of Py phosphorylation, including the possible involvement of Ca2+/Ca2+-binding proteins.
Yamazaki
Akio
A
Department of Ophthalmology, Kresge Eye Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
Moskvin
Oleg
O
Yamazaki
Russell K
RK
D020816:Amino Acid Motifs; D000818:Animals; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006868:Hydrolysis; D008954:Models, Biological; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012160:Retina / Q000378:metabolism*
D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases; D010727:Phosphoric Diester Hydrolases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human