Activation of PDE10 and PDE11 Phosphodiesterases

Doris Koesling,Frank Schwede,Michael Russwurm,Corina Russwurm,Ronald Jäger,Hans-Gottfried Genieser

doi:10.1074/jbc.m111.263806

Doris Koesling, Frank Schwede + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m111.263806

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Abstract

The most recently identified cyclic nucleotide phosphodiesterases, PDE10 and PDE11, contain a tandem of so-called GAF domains in their N-terminal regulatory regions. In PDE2 and PDE5, the GAF domains mediate cGMP stimulation; however, their function in PDE10 and PDE11 remains controversial. Although the GAF domains of PDE10 mediate cAMP-induced stimulation of chimeric adenylyl cyclases, cAMP binding did not stimulate the PDE10 holoenzyme. Comparable data about cGMP and the PDE11 GAF domains exist. Here, we identified synthetic ligands for the GAF domains of PDE10 and PDE11 to reduce interference of the GAF ligand with the catalytic reaction of PDE. With these ligands, GAF-mediated stimulation of the PDE10 and PDE11 holoenzymes is demonstrated for the first time. Furthermore, PDE10 is shown to be activated by cAMP, which paradoxically results in potent competitive inhibition of cGMP turnover by cAMP. PDE11, albeit susceptible to GAF-dependent stimulation, is not activated by the native cyclic nucleotides cAMP and cGMP. In summary, PDE11 can be stimulated by GAF domain ligands, but its native ligand remains to be identified, and PDE10 is the only PDE activated by cAMP.

Highlights

The cyclic nucleotide phosphodiesterases PDE10 and PDE11 contain putatively regulatory GAF domains with unknown function
The GAF-containing PDE2 and PDE5 are allosterically activated by cGMP
GAF-dependent activation of PDE10 and PDE11 has not been demonstrated; this may be partially due to the fact that the nucleotide serving as the GAF ligand is degraded as a substrate

Summary

Background

The cyclic nucleotide phosphodiesterases PDE10 and PDE11 contain putatively regulatory GAF domains with unknown function. The most recently identified cyclic nucleotide phosphodiesterases, PDE10 and PDE11, contain a tandem of so-called GAF domains in their N-terminal regulatory regions. PDE11, albeit susceptible to GAF-dependent stimulation, is not activated by the native cyclic nucleotides cAMP and cGMP. A recent publication claimed that binding of cyclic nucleotides to the PDE10 and PDE11 GAF domains does not stimulate catalytic activity [27]. In another experimental approach, the PDE10 and -11 GAF domains fused to the catalytic domain of a bacterial adenylyl cyclase were studied. We used fluorophore-tagged tandem GAF domains of PDE10 and PDE11 to identify synthetic GAF ligands Using these ligands, GAF-mediated stimulation of PDE10 and PDE11 is demonstrated. Our results show that cAMP activation of PDE10 enhances competitive inhibition of cGMP turnover by cAMP and that PDE11, despite its activation by synthetic GAF ligands, is not stimulated by the physiological cyclic nucleotides cAMP and cGMP

EXPERIMENTAL PROCEDURES

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DISCUSSION