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First published online June 28, 2004
doi: 10.1242/10.1242/jcs.01295

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New aspects of nuclear calcium signalling

MRC Secretory Control Research Group, The Physiological Laboratory, University of Liverpool, Crown Street, Liverpool L69 3BX, UK

View larger version (64K): [in a new window]   Fig. 1. Transient nuclear-cytoplasmic Ca2+ gradients in pancreatic acinar cells [modified figure reproduced with permission from Springer-Verlag (Gerasimenko et al., 1996b)]. (A) A typical localized Ca2+ spike induced by the short application of acetylcholine (ACh) in the secretory granule area does not enter the nucleus or basal area of a doublet of pancreatic acinar cells: the first image is the transmitted light picture, the second image is the same cluster, stained with the nuclear dye Hoechst 33342. Yellow boxes, secretory granule areas; blue boxes, nuclei; purple boxes, basal areas. Colour images show confocal recording of propagation of Ca2+ spike in time (two images per second) from left to right. Cells were stained with Fura Red in AM form. Bar, 5 µs. (B) Traces of Ca2+ concentration changes: upper traces are for secretory granule area (yellow boxes in A), middle traces are from the nuclei (blue boxes in A), lower traces are from the basal areas (purple boxes in A). (C) A long application of ACh induces global responses in the same cluster. The Ca2+ concentration in the nucleus only temporarily differs from that in the cytoplasm. Bar, 5 µm. (D) The temporary Ca2+ gradient along the line between nucleus and cytoplasm during a local Ca2+ spike can be quite high: 400 nM/µm. (I) Transmitted light picture of the cell. Dark areas correspond to secretory granules. [Ca2+] was measured along the diagonal line. Bar, 5 µm. (II) Position of the nucleus was verified by staining with Hoechst 33342. (III) The graph corresponds to changes of [Ca2+] along the line shown in I; 1 at rest, 2 at the peak of the local Ca2+ response. N indicates the position of the nucleus.

View larger version (38K): [in a new window]   Fig. 2. The NE is a Ca2+ store that allows access of ions to the cytoplasm through the NPCs [modified figure reproduced with permission from Elsevier (Gerasimenko et al., 1995)]. (A) Nucleus loaded with Fura 2 in the acetoxymethyl (AM) ester form. Only NE is loaded with Ca2+ dye. (B) Nucleus is loaded with Calcium Green dextran, accumulated in the nucleoplasm. (C) Model of Ca2+ store in the NE. The NE is freely accessible to ions through NPCs and can release Ca2+ directly into nucleoplasm. cADPR, cyclic ADP-ribose; INM, inner nuclear membrane; IP3, inositol (1,4,5)-trisphosphate; ONM, outer nuclear membrane. Bars, 5 µm.

View larger version (18K): [in a new window]   Fig. 3. Morphology of the NE Ca2+ store in pancreatic acinar nuclei [modified figure reproduced with permission from The Rockefeller University Press (Gerasimenko et al., 2003)]. (A) Two nuclei stained with Mag Fura Red in the AM form – a Ca2+ dye used for NE Ca2+ store measurements. (B) Staining of the same nuclei with BODIPY-thapsigargin – an ER-specific dye. (C) Overlay of images shown in A and B. (D) Staining of nucleus with fluorescent BODIPY FL ryanodine. Bars in A (for A-C) and D, 4 µm.

View larger version (36K): [in a new window]   Fig. 4. Simplified model of Ca2+ release in the NE and surrounding ER: three intracellular Ca2+ messengers use two intracellular Ca2+ receptors for Ca2+ release from a single unified store [modified figure reproduced with permission from The Rockefeller University Press (Gerasimenko et al., 2003)]. Ca2+ released from the NE enters the nucleoplasm either directly through Ins(1,4,5)P3Rs or RyRs in the inner nuclear membrane (INM) or through the NPCs when released through Ins(1,4,5)P3Rs or RyRs in the outer nuclear membrane (ONM). Three messengers can be produced locally inside the NE: Ins(1,4,5)P3 generated by phospholipase C (PLC) or cADPR and NAADP generated by the CD38/ADP ribosyl cyclase (ARC). cADPR and NAADP bind different binding sites or receptors (marked by?) and activate RyR Ca2+ channels. All three Ca2+ messengers can also be produced in the cytosol and then enter the nucleoplasm through the NPCs. Ca2+ is pumped into the NE and ER by the sarco-endoplasmic reticulum Ca2+-activated ATPase (SERCA) on the ONM. IP3R, inositol (1,4,5)-trisphosphate receptor.