Figure 2.

Working hypotheses to trigger nuclear Ca²⁺

Different pathways to generate nuclear Ca²⁺ signals have been proposed. In 1 (left), the binding of an agonist to its transmembrane G-protein-coupled receptor (GPCR) produces InsP₃ (IP₃) in the cytosol. IP₃ diffuses to the nucleus and binds to the high-affinity, type II InsP₃R (IP₃R-II), located along the nucleoplasmic reticulum (NR), to release Ca²⁺ in the nucleoplasm. In 2 (middle), the binding of a growth factor to a receptor tyrosine kinase (TKR) may result in the translocation of the receptor to the nucleus to generate nuclear IP₃. IP₃ binds to the IP₃R to release Ca²⁺ in the nucleoplasm. The topology of internalized TRK is not known, and the cartoon shows TKR as being inside the vesicle merely for simplicity. In 3 (right), another putative pathway is initiated following the binding of a hormone to GPCR at the plasma membrane. The IP₃ generated within the cytosol can release Ca²⁺ from the endo-/sarcoplasmic reticulum, and Ca²⁺ may reach the nucleus to trigger Ca²⁺-induced Ca²⁺ release by activating the ryanodine receptor (RyR) in the NR.