It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods

• Main Authors: Bilal M. Qureshi, Elmar Behrmann, Johannes Schöneberg, Justus Loerke, Jörg Bürger, Thorsten Mielke, Jan Giesebrecht, Frank Noé, Trevor D. Lamb, Klaus Peter Hofmann, Christian M. T. Spahn, Martin Heck
• Format: Article
• Language: English
• Published: The Royal Society 2018-08-01
• Series: Open Biology
• Subjects: pde6; visual signal transduction; coincidence switch; density switch; noise filtering
• Online Access: https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.180075

Among cyclic nucleotide phosphodiesterases (PDEs), PDE6 is unique in serving as an effector enzyme in G protein-coupled signal transduction. In retinal rods and cones, PDE6 is membrane-bound and activated to hydrolyse its substrate, cGMP, by binding of two active G protein α-subunits (Gα*). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction–diffusion simulations. Gα* titration of membrane-bound PDE6 reveals a strong functional asymmetry of the enzyme with respect to the affinity of Gα* for its two binding sites on membrane-bound PDE6 and the enzymatic activity of the intermediary 1 : 1 Gα* · PDE6 complex. Employing cGMP and its 8-bromo analogue as substrates, we find that Gα* · PDE6 forms with high affinity but has virtually no cGMP hydrolytic activity. To fully activate PDE6, it takes a second copy of Gα* which binds with lower affinity, forming Gα* · PDE6 · Gα*. Reaction–diffusion simulations show that the functional asymmetry of membrane-bound PDE6 constitutes a coincidence switch and explains the lack of G protein-related noise in visual signal transduction. The high local concentration of Gα* generated by a light-activated rhodopsin molecule efficiently activates PDE6, whereas the low density of spontaneously activated Gα* fails to activate the effector enzyme.