THE CALMODULIN-DEPENDENT PHOSPHODIESTERASE GENE PDE1C ENCODES SEVERALFUNCTIONALLY DIFFERENT SPLICE VARIANTS IN A TISSUE-SPECIFIC MANNER

We report here the identification of cDNAs for three new mouse PDE1C s plice variants and the characterization of their kinetics, regulation by Ca2+, sensitivities to inhibitors, and tissue/cellular expression p atterns. Sequence analysis indicated that these three cDNAs (PDE1C1, P DE1C4, and PDE1C5), together with our previously reported PDE1C2 and P DE1C3, are alternative splice products of the PDE1C gene. The results from RNase protection analysis and in situ hybridization indicated tha t the expression of the different PDE1C splice variants is differentia lly regulated in a tissue/cell-specific manner. Particularly, high lev els of PDE1C mRNAs were found in the olfactory epithelium, testis, and several regions of mouse brain such as cerebellar granule cells, All of these splice variants have similar kinetic properties, showing high affinities and approximately the same relative V-max values for both cAMP and cGMP. However, they responded to Ca2+ stimulation differently , In addition, they show different sensitivities to the calmodulin-dep endent phosphodiesterase inhibitors, KS505a and SCH51866. Substrate co mpetition experiments suggested the presence of only one catalytic sit e on these PDE1C isozymes for both cAMP and cGMP. In summary, these fi ndings suggest that the PDE1C gene undergoes tissue-specific alternati ve splicing that generates structurally and functionally diverse gene products.