Nuclear Ca²⁺: physiological regulation and role in apoptosis

Abstract

The last decade has seen the rapid development of research investigating the molecular mechanisms whereby hormones, peptide growth factors and cytokines regulate cell metabolism, differentiation and proliferation. One general signalling mechanism used to transfer the information delivered by agonists into appropriate intracellular compartments involves the rapid Ca²⁺ redistribution throughout the cell, which results in transient elevations of the cytosolic free Ca²⁺ concentration. Ca²⁺ signals are required for a number of cellular processes including the activation of nuclear processes such as gene transcription and cell cycle events. The latter require that appropriate Ca²⁺ signals elicited in response to agonists be transduced across the nuclear envelope. It has generally been assumed that small molecules, metabolites and ions could freely diffuse across the nuclear envelope. Nevertheless several findings during the past few years have suggested that nuclear pore permeability can be regulated and that ion transport systems and ion-selective channels may exist on the nuclear membranes and regulate intranuclear processes.

Intranuclear Ca²⁺ fluctuations can affect chromatin organization, induce gene expression and also activate cleavage of nuclear DNA by nucleases during programmed cell death or apoptosis. The possible mechanisms involved in nuclear Ca²⁺ transport and the control of nuclear Ca²⁺-dependent enzymes in apoptosis is discussed below.