Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A

We report here the cloning, expression, and characterization of a dual-substrate, cAMP and cGMP, cyclic nucleotide phosphodiesterase (PDE) from mouse. This PDE contains the consensus sequence for a PDE catalytic domain, but shares <50% sequence identity with the catalytic domains of all other known PDEs and, therefore, represents a new PDE gene family, designated PDE10A, The cDNA for PDE10A is 3,370 nt in length. It includes a full ORF, contains three in-frame stop codons upstream of the first methionine, and is predicted to encode a 779-aa enzyme. At the N terminus PDE10A has two GAF domains homologous to many signaling molecules, including PDE2, PDES, and PDE6, which likely constitute a low-affinity binding site for cGMP, PDE10A hydrolyzes cAMP with a K-m of 0.05 mu M and cGMP with a K-m of 3 mu M. Although PDE10A has a lower K-m for cAMP, the V-max ratio (cGMP/cAMP) is 4.7, RNA distribution studies indicate that PDE10A is expressed at highest levels in testis and brain.