The cell cycle: a new entry in the field of Ca2+ signaling.

Ca2+ signaling plays a crucial role in virtually all cellular processes, from the origin of new life at fertilization to the end of life when cells die. Both the influx of external Ca2+ through Ca2+-permeable channels and its release from intracellular stores are essential to the signaling function. Intracellular Ca2+ is influenced by mitogenic factors which control the entry and progression of the cell cycle; this is a strong indication for a role of Ca2+ in the control of the cycle, but surprisingly, the possibility of such a role has only been paid scant attention in the literature. Substantial progress has nevertheless been made in recent years in relating Ca2+ and the principal decoder of its information, calmodulin, to the modulation of various cycle steps. The aim of this review is to critically discuss the evidence for a role of Ca2+ in the cell cycle and to discuss Ca2+-dependent pathways regulating cell growth and differentiation.

Ca2+ signalling and membrane current activated by cADPr in starfish oocytes.

Cyclic ADP-ribose (cADPr) is a second messenger that regulates intracellular free [Ca2+] ([Ca2+](i)) in a variety of cell types, including immature oocytes from the starfish Astropecten auranciacus. In this study, we employed confocal laser scanning microscopy and voltage clamp techniques to investigate the source of the cADPr-elicited Ca2+ wave originating from the cortical Ca2+ patches we have described previously. The Ca2+ swing was accompanied by a membrane current with a reversal potential of approximately +20 mV. Decreasing external Na+ almost abolished the current without affecting the Ca2+ response. Removal of extracellular Ca2+ altered neither the Ca2+ transient nor the ionic current, nor did the holding potential exert any effect on the Ca2+ wave. Both the Ca2+ response and the membrane current were abolished when BAPTA, ruthenium red or 8-NH(2)-cADPr were preinjected into the oocytes, while perfusion with ADPr did not elicit any [Ca2+](i) increase or ionic current. However, elevating [Ca2+](i) by uncaging Ca2+ from nitrophenyl- (NP-EGTA) or by photoliberating inositol 1,4,5-trisphosphate (InsP(3)) induced an ionic current with biophysical properties similar to that elicited by cADPr. These results suggest that cADPr activates a Ca2+ wave by releasing Ca2+ from intracellular ryanodine receptors and that the rise in [Ca2+](i) triggers a non-selective monovalent cation current that does not seem to contribute to the global Ca2+ elevation.

Activated M-phase-promoting factor (MPF) is exported from the nucleus of starfish oocytes to increase the sensitivity of the Ins(1,4,5)P3 receptors.

Starfish oocytes that are extracted from the ovaries are arrested at the prophase of the first meiotic division. At this stage of maturation, they are characterized by a large nucleus called the germinal vesicle. Meiosis resumption (maturation) can be induced in vitro by adding the hormone 1-methyladenine (1-MA) to the seawater in which the oocytes are suspended. Earlier work in our laboratory had detected Ca(2+) increases in both the cytoplasm and the nucleus of the oocytes approx. 2 min after the 1-MA challenge. The nuclear Ca(2+) increase was found to be essential for the continuation of the meiotic cycle, since the injection of bis-(o-aminophenoxy)ethane- N,N,N',N' -tetra-acetic acid (BAPTA) into the nuclear compartment completely blocked the re-initiation of the cell cycle. We have recently confirmed, using confocal microscopy, that the cytoplasmic and nuclear Ca(2+) pools are regulated independently and that the nuclear envelope in starfish oocytes is not freely permeated by the Ca(2+) wave that sweeps across the nuclear region. Studies by others have shown that the sensitivity of the Ins(1,4,5) P (3) (IP(3)) receptors (IP(3)Rs) to IP(3) increases during oocyte maturation, so that they release progressively more calcium in response to the injection of IP(3), as maturation proceeds. We have now shown that the increased sensitivity of the IP(3)Rs may depend on the activation of the cyclin-dependent kinase, MPF (M-phase-promoting factor) that occurs in the nucleus. MPF does not directly phosphorylate IP(3)Rs but phosphorylates instead the actin-binding protein actin depolymerization factor (ADF)/cofilin.