title: Phosphodiesterase 10A Is Tethered to a Synaptic Signaling Complex in Striatum.
abstract: Phosphodiesterase 10A (PDE10A) is a dual substrate PDE that can hydrolyze both cGMP and cAMP. In brain, PDE10A is almost exclusively expressed in the striatum. In several studies, PDE10A has been implicated in regulation of striatal output using either specific inhibitors or PDE10A knock-out mice and has been suggested as a promising target for novel antipsychotic drugs. In striatal medium spiny neurons, PDE10A is localized at the plasma membrane and in dendritic spines close to postsynaptic densities. In the present study, we identify PDE10A as the major cAMP PDE in mouse striatum and monitor PKA-dependent PDE10A phosphorylation. With recombinantly expressed PDE10A we demonstrate that phosphorylation does not alter PDE10A activity. In striatum, PDE10A was found to be associated with the A kinase anchoring protein AKAP150 suggesting the existence of a multiprotein signaling complex localizing PDE10A to a specific functional context at synaptic membranes. Furthermore, the cAMP effector PKA, the NMDA receptor subunits NR2A and -B, as well as PSD95, were tethered to the complex. In agreement, PDE10A was almost exclusively found in multiprotein complexes as indicated by migration in high molecular weight fractions in size exclusion chromatography. Finally, affinity of PDE10A to the signaling complexes formed around AKAP150 was reduced by PDE10A phosphorylation. The data indicate that phosphorylation of PDE10 has an impact on the interaction with other signaling proteins and adds an additional line of complexity to the role of PDE10 in regulation of synaptic transmission.
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität-Bochum, 44780 Bochum, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Russwurm
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität-Bochum, 44780 Bochum, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Koesling
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität-Bochum, 44780 Bochum, Germany michael.russwurm@ruhr-uni-bochum.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Russwurm
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D015971:Gene Expression Regulation, Enzymologic; D051528:Guanylate Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D051528:Guanylate Kinases; C119843:PDE10A protein, human; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D002118:Calcium
keywords: A-kinase Anchoring Protein (AKAP); Cell Signaling; Cyclic AMP (cAMP); Phosphodiesterases; Protein Complex; Protein Kinase A (PKA)