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

Open Biol. 2018 Aug;8(8):180075. doi: 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.

Keywords: PDE6; coincidence switch; density switch; noise filtering; visual signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cattle
  • Cell Membrane / metabolism
  • Cyclic GMP / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / chemistry
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism*
  • Enzyme Activation
  • Hydrolysis
  • Protein Binding
  • Retinal Rod Photoreceptor Cells / metabolism*
  • Transducin / chemistry
  • Transducin / metabolism*


  • Cyclic Nucleotide Phosphodiesterases, Type 6
  • Transducin
  • Cyclic GMP