We previously found that the nitric oxide (NO)-cGMP-cGMP-dependent protein kinase (PKG) signaling pathway acts in parallel with the cAMP-cAMP-dependent protein kinase (PKA) pathway to produce protein and RNA synthesis-dependent late-phase long-term potentiation (L-LTP) and cAMP response element-binding protein (CREB) phosphorylation in the CA1 region of mouse hippocampus. We have now investigated the possible involvement of a downstream target of PKG, ryanodine receptors. L-LTP can be induced by either multiple-train tetanization, NO or 8-Br-cGMP paired with one-train tetanization, or the cAMP activator forskolin, and all three types of potentiation are accompanied by an increase in phospho-CREB immunofluorescence in the CA1 cell body area. Both the potentiation and the increase in phospho-CREB immunofluorescence induced by multiple-train tetanization or 8-Br-cGMP paired with one-train tetanization are reduced by prolonged perfusion with ryanodine, which blocks Ca(2+) release from ryanodine-sensitive Ca(2+) stores. By contrast, neither the potentiation nor the increase in immunofluorescence induced by forskolin are reduced by depletion of ryanodine and inositol-1,4,5-triphosphate (IP3)-sensitive Ca(2+) stores. These results suggest that NO, cGMP, and PKG cause release of Ca(2+) from ryanodine-sensitive stores, which in turn causes phosphorylation of CREB in parallel with PKA during the induction of L-LTP.