A cDNA clone for cyclic GMP Stimulated Phosphodiesterase (cGSPDE; PDE2) was isolated from a rat brain cDNA library. The cDNA has an open reading frame which encodes a protein of 928 amino acids of which 829 are identical with the reported bovine adrenal gland cGSPDE cDNA (Sonnenburg, W.K., Mullaney, P.J., and Beavo, J.A. (1991) J. Biol. Chem. 266, 17655-17661). Although the overall homology of these two cDNAs is high, they are distinctly different in their 5' ends, with the N-terminal 37 amino acids of the rat brain protein showing no homology with the N-terminal end of the bovine adrenal protein. Hydrophilicity plots show that in contrast to the bovine adrenal cGSPDE, the N-terminal end of the rat brain cGSPDE is highly hydrophobic. Isolation and analysis of a genomic clone for cGSPDE from a rat genomic library shows the presence of an exon/intron junction at the Gln39 codon. The cGSPDE cDNA we have isolated and that of Sonnenburg et al. represent alternatively spliced mRNA products from the same gene, with the brain isoform designed to be targeted to membranes.