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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number180075
JournalOpen Biology
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2018

Keywords

  • PDE6
  • coincidence switch
  • density switch
  • noise filtering
  • visual signal transduction

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience
  • Immunology

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