PDE6 is the central effector of the visual signaling pathway in rods and cones
The first step in vertebrate vision is the photoisomerization of 11-cis retinal to the all-trans isomer which is covalently bound to the G-protein-coupled receptor, rhodopsin. Upon activation, rhodopsin undergoes a conformational change in its cytoplasmic loops that facilitates binding and activation of the heterotrimeric G-protein, transducin. The activated α-subunit of transducin (Tα*-GTP) then binds to the inactive PDE6 holoenzyme and displaces its inhibitory γ-subunit. PDE6 activation accelerates cGMP hydrolysis, resulting in a rapid drop in cytoplasmic cGMP levels. cGMP-gated ion channels in the plasma membrane which were open in the dark-adapted state then dissociate their liganded cGMP, causing channel closure and membrane hyperpolarization.
While the basic pathway of visual transduction described above is generally accepted, the protein-protein interactions and allosteric regulation that occur during activation and deactivation of PDE6 are poorly understood. Further, the biochemical mechanisms underlying light adaptation are not well delineated, but there is strong evidence that additional mechanisms of PDE6 regulation play a role in photoresponse desensitization. Our lab is integrating biochemical approaches with structural analyses of the macromolecular PDE6 signaling complex in order to define the sequence of steps in the activation, inactivation, and adaptation of the complex of PDE6 and its interacting partners during visual signaling.
While the basic pathway of visual transduction described above is generally accepted, the protein-protein interactions and allosteric regulation that occur during activation and deactivation of PDE6 are poorly understood. Further, the biochemical mechanisms underlying light adaptation are not well delineated, but there is strong evidence that additional mechanisms of PDE6 regulation play a role in photoresponse desensitization. Our lab is integrating biochemical approaches with structural analyses of the macromolecular PDE6 signaling complex in order to define the sequence of steps in the activation, inactivation, and adaptation of the complex of PDE6 and its interacting partners during visual signaling.
