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

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 alpha-subunits (G alpha*). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction-diffusion simulations. G alpha* titration of membrane-bound PDE6 reveals a strong functional asymmetry of the enzyme with respect to the affinity of G alpha* for its two binding sites on membrane-bound PDE6 and the enzymatic activity of the intermediary 1 : 1 G alpha*. PDE6 complex. Employing cGMP and its 8-bromo analogue as substrates, we find that G alpha*. PDE6 forms with high affinity but has virtually no cGMP hydrolytic activity. To fully activate PDE6, it takes a second copy of G alpha* which binds with lower affinity, forming G alpha*. PDE6. G alpha*. 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 G alpha* generated by a light-activated rhodopsin molecule efficiently activates PDE6, whereas the low density of spontaneously activated G alpha* fails to activate the effector enzyme.