title: Activation of PDE10 and PDE11 phosphodiesterases.
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.
authors: Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany.
authors: Ronald
authors: R
authors: Jäger
authors: Corina
authors: C
authors: Russwurm
authors: Frank
authors: F
authors: Schwede
authors: Hans-Gottfried
authors: HG
authors: Genieser
authors: Doris
authors: D
authors: Koesling
authors: Michael
authors: M
authors: Russwurm
mesh_terms: D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D057809:HEK293 Cells; D020035:Holoenzymes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D020035:Holoenzymes; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP