Figure 5.

Proposed presynaptic, NO-triggered cascade for the induction of LTD. The cascade begins with calcium entry via N-methyl-d-aspartate receptors (NMDAR), voltage-dependent calcium channels (VDCC), and metabotropic glutamate receptor-triggered, inositol trisphosphate-mediated release of stored calcium, which activates Ca²⁺/calmodulin-dependent nitric oxide synthase (NOS). NOS produces the retrograde messenger nitric oxide (NO), which diffuses to the presynaptic terminal and activates soluble guanylate cyclase (GC) to generate cGMP. One target of cGMP is PKG, which, when activated, can phosphorylate serine/threonine residues. One potential target of PKG is ADP-ribosyl cyclase/hydrolase (ARC; CD38), which produces cADPR from β-NAD⁺. Finally, cADPR facilitates release of calcium from intracellular stores by binding to RyRs on these stores. IP₃R, inositol trisphosphate receptor.