Low levels of cyclic GMP phosphodiesterase (PDE) coupled with insufficient amount of calmodulin in retinas of Irish setter dogs with inherited degeneration could be responsible for the high concentrations of cyclic GMP presented in these degenerated dog retinas. The relationship of the retinal degeneration and cyclic GMP PDE and calmodulin was also investigated in hereditary retinopathy in collies. Cyclic GMP PDE levels rose as outer segments developed in the control dogs, while in the affected animals, cyclic GMP PDE levels were generally low, and the molecular form of cyclic GMP PDE is Ca ion and calmodulin-independent. In bovine retina extracts, cyclic CMP PDE may be a separate enzyme distinguishable from cyclic AMP PDE and cyclic GMP PDE on the basis of differential inhibition by PDE inhibitors.