An update on nuclear calcium signalling

Abstract

Over the past 15 years or so, numerous studies have sought to characterise how nuclear calcium (Ca 2+ ) signals are generated and reversed, and to understand how events that occur in the nucleoplasm influence cellular Ca 2+ activity, and vice versa. In this Commentary, we describe mechanisms of nuclear Ca 2+ signalling and discuss what is known about the origin and physiological significance of nuclear Ca 2+ transients. In particular, we focus on the idea that the nucleus has an autonomous Ca 2+ signalling system that can generate its own Ca 2+ transients that modulate processes such as gene transcription. We also discuss the role of nuclear pores and the nuclear envelope in controlling ion flux into the nucleoplasm. Journal of Cell Science 2338(which would cause its nuclear export) and through a physical interaction that occludes a nuclear-export sequence (NES) in the NFAT protein.An example of a nuclear-localised transcription factor that is regulated by both nuclear and cytosolic Ca 2+ signals is cyclic AMP response element-binding protein (CREB). The signalling mechanisms that underlie CREB activation have been worked out particularly well in neurons, in which it has been established that depolarisation leads to the rapid phosphorylation of CREB on Ser133 by Ca 2+ -calmodulin-dependent kinase IV, which provides a necessary, but not sufficient, signal for CREB-mediated gene transcription (Dolmetsch et al., 2001). The triggering event is an increase in cytosolic Ca 2+ levels in the immediate vicinity of L-type Ca 2+ channels or N-methyl-D-aspartate receptors that are found in the synapse, at a site that is distal to the nucleus (Shaywitz and Greenberg, 1999). As CREB is only found in the nucleus, the phosphorylation of Ser133 is mediated by one of several Ca 2+ -sensitive signal transduction cascades that convey information from the remote synapses into the nucleus. In the nucleus, phosphorylated CREB binds additional proteins to form a transcriptionally active complex (Shaywitz and Greenberg, 1999). Although the synaptic Ca 2+ signal does not need to propagate to the nucleus to induce phosphorylation of Ser133 on CREB, an increase in the level of nuclear Ca 2+ is required for CREB-mediated gene transcription to occur. This is because additional Ca 2+ -dependent phosphorylation of CREB and its co-activators is required (Chawla et al., 1998;Kornhauser et al., 2002). Indeed, nuclear injection of an artificial Ca 2+ buffer prevents CREB-mediated gene transcription, but not transcription induced by the serum-response element, which is sensitive to cytosolic Ca 2+ buffering (Hardingham et al., 1997).Another well-known target of nuclear Ca 2+ signalling is the transcriptional regulator downstream regulatory element antagonist modulator (DREAM). It is well established that DREAM represses the expression of prodynorphin, an opiate-receptor precursor, and that mice that lack DREAM have a constitutive analgesic condition (Cheng et al., 2002). DREAM contains four Ca 2+ -binding EF hands (a widely expressed structural mo...

Regulation of nuclear envelope permeability in cell death and survival

“…To account for the asynchronicity of the apoptotic process, data from each time series were split into two parts and displayed Numerous studies have proposed a role for Ca 2+ in the regulation of NPC structure and function. The underlying mechanisms are not fully clear yet (reviewed in [20][21][22] ). The NE harbours functional inositol(1,4,5)-trisphosphate receptors (InsP3Rs), as well as ryanodine receptors (RyRs) and nicotinic acid adenine dinucleotide phosphate receptors (NAADPRs).…”

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…Similarly, the ETB-selective agonist IRL-1620 increases [Ca 2+ ] n in nuclei isolated from rat heart [12] and liver [89]. This release of Ca 2+ represents activation of calcium channels within the inner nuclear membranes (see [90]); however, the actual mechanism whereby [Ca 2+ ] n was increased was not assessed. We have now shown that treatment of intact ventricular myocytes with a caged ET-1 analog also induced an IP3R-mediated increase in [Ca 2+ ] n .…”

Calpain-1 Cleaves Rad21 To Promote Sister Chromatid Separation

“…Thus, an increase in extracellular [Ca 2ϩ ] is expected to increase the intracellular [Ca 2ϩ ] (4). Increased cytoplasmic Ca 2ϩ is likely to diffuse into the nucleus, resulting in increased nuclear [Ca 2ϩ ] (3,6). This can consequently lead to activation of nuclear calpain-1.…”