We have recently reported increased survival of dopaminergic substantia nigra neurons by inhibition of phosphodiesterase type IV enzymes. As a first step to unravel the involvement of PDE IV subtypes in this process, we isolated phosphodiesterase type IV cDNAs from human substantia nigra. One isolated partial cDNA clone was most homologous to the partially cloned rat and human PDE IV-C isogene. Distribution analysis revealed that the enzyme is expressed in various tissues but not in cells of the immune system. Isolation of the full-length human PDE IV-C isogene cDNA and expression in a PDE-deficient yeast strain resulted in functional complementation of the yeast heat shock response. Inhibition of the enzymatic activity by rolipram characterized this enzyme as a typical type IV phosphodiesterase.