Decoding calcium signaling across the nucleus

Abstract

Calcium (Ca(2+)) is an important multifaceted second messenger that regulates a wide range of cellular events. A Ca(2+)-signaling toolkit has been shown to exist in the nucleus and to be capable of generating and modulating nucleoplasmic Ca(2+) transients. Within the nucleus, Ca(2+) controls cellular events that are different from those modulated by cytosolic Ca(2+). This review focuses on nuclear Ca(2+) signals and their role in regulating physiological and pathological processes.

Figure 1.

The nucleus contains the nucleoplasmic reticulum structure The nuclear envelope was labeled with an antibody against lamin-A (green) in SkHep1 (A), an adenocarcinoma liver cell line, and freshly isolated primary hepatocytes treated (B) or not treated (C) with staurosporine (STA) for 4 h, respectively. DNA was stained with propidium iodide. Note the presence of the nucleoplasmic reticulum (NR) in a cell line as well as in a primary culture. In the two top panels, the images represent three focal planes, depicting the three dimensionality of the NR. In the cell lineage used here, the NR seems to be constitutively present (A). In the primary culture of hepatocytes, the NR, not present under control condition, can be induced by drugs, such as STA (compare B with C), corroborating the findings that the NR is a dynamic and inducible structure. Bar in A = 5 μm; bars in B and C = 10 μm.

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.