Nuclear calcium and the regulation of the nuclear pore complex

Abstract

In eukaryotic cells the nucleus and its contents are separated from the cytoplasm by the nuclear envelope. Macromolecules, as well as smaller molecules and ions, can cross the nuclear envelope through the nuclear pore complex. Molecules greater than approx. 60 kDa and containing a nuclear localization signal are actively transported across the nuclear membranes, but there has been little evidence for regulatory mechanisms for smaller molecules and ions. Recently, diffusion across the nuclear envelope has been observed to be regulated by nuclear cisternal Ca2+ concentrations. Following depletion of Ca2+ from the nuclear store by inositol 1,4,5-trisphosphate or Ca2+ chelators, a fluorescent 10 kDa marker molecule was no longer able to enter the nucleus. Distinct conformational states of the nuclear pore complexes depended on the Ca2+ filling state of the nuclear envelope, supporting the assumption that a switch in the conformation of the nuclear pore complex may control the transport of intermediate-sized molecules across the nuclear envelope. Thus nuclear Ca2+ stores may regulate the conformational state of the nuclear pore complex, and thereby passive diffusion of molecules between the cytosol and the nucleoplasm. The physiological significance of this finding is currently unknown.

The HIV Nef Protein Alters Ca2+ Signaling in Myelomonocytic Cells through SH3-mediated Protein-Protein Interactions

“…In addition, Nef could alter other cellular functions independent of an extracellular Ca 2ϩ influx but which may be regulated by the Ca 2ϩ content of the endoplasmic reticulum. Indeed, the Ca 2ϩ content of the endoplasmic reticulum plays an important role in protein synthesis (60,61), regulation of apoptosis (62,63), gene expression (64), and regulation of the nuclear pore activity (65). Future studies will have to address the question of how the Nefinduced increase in intracellular Ca 2ϩ storage and the subsequent potential effects relate to the specific properties of HIV infection in myelomonocytic cells.…”

Binding of Ca2+ and Zn2+ to Human Nuclear S100A2 and Mutant Proteins

“…Even in the dimeric state, S100A2 is small enough to enter the nucleoplasm via the nuclear pore complex by passive diffusion (for a review, see Ref. 43). Nuclear accumulation may occur if S100A2 is selectively retained through binding to a nondiffusible component in the nucleoplasm, thus offering a plausible explanation why S100A2 is predominantly found in the nucleus.…”

Nucleocytoplasmic trafficking

“…Others have suggested that this feature is a preparative artifact because it was not observed in other experiments and was postulated to be molecular cargo trapped in transit (35). Numerous studies investigating the role of calcium in NPC regulation, however, have demonstrated a calcium-sensitive mechanism responsible for closing and opening the pore (17,18). These independent observations support the notion that the NPC is dynamically regulated by calcium fluxes in and around the nucleus (17,18,38).…”

“…Electron microscopy of prepared NEs illustrates the octagonal symmetry of the pore when viewed en face. The central pore can dilate to accommodate larger cargoes in transit (15,16) as well as respond to calcium fluxes (17,18). In addition to the main central channel (19,20), peripheral channels exist, which are hypothesized to permit the flow of various small molecules and ions (4,21).…”

“…The presence or absence of the central transporter in response to the depletion or repletion of periplasmic calcium stores, respectively, is an excellent example of NPC dynamics (17,18). It has been proposed that this transporter -or 'plug' -may represent a calcium-sensitive multimer composed of nup gp210 (32).…”