Role of cyclic GMP in signal transduction to cytoskeletal myosin.

Evidence is presented for cyclic GMP having a role as a secondary messenger connecting the cell surface cyclic AMP receptors and cytoskeletal myosin II involved in chemotaxis of amoebae of Dictyostelium. Studies were conducted using mutants whose primary defect is in the structural gene for the cyclic GMP-specific phosphodiesterase (streamer F mutants). These mutants show abnormally prolonged accumulation of cyclic GMP in response to stimulation with the chemoattractant cyclic AMP. Investigation of signal transduction in these mutants indicated that, while events associated with production and relay of cyclic AMP signals were normal, certain events associated with movement were (like the cyclic GMP response) abnormally prolonged and these included myosin II association with the cytoskeleton and inhibition of myosin heavy and light chain phosphorylation. These events can be correlated with the amoebae becoming elongated and transiently decreasing their locomotive speed after chemotactic stimulation. Other mutants studied in which the accumulation of cyclic GMP was reduced or absent produced correspondingly reduced or absent myosin responses. We propose a model in which cyclic GMP (transiently accumulated intracellularly in response to stimulation with extracellular cyclic AMP) induces accumulation of myosin II on the cytoskeleton by inhibiting phosphorylation of the myosin heavy chain. As a consequence, bending of the myosin tail and its dissociation from the cytoskeleton are inhibited.