Calcium at the Crossroads of Signaling

Abstract

Cells must respond to an array of environmental and developmental cues. The signaling networks that have evolved to generate appropriate cellular responses are varied and are normally composed of elements that include a sequence of receptors, nonprotein messengers, enzymes and transcription factors. Receptors are normally highly specific for the physiological stimulus, and therefore are disparate in their identities. Likewise enzymes and transcription factors tend toward specificity, and this fact is reflected in abundance at the genome level. The Arabidopsis genome, for example, potentially encodes in the region of 1000 protein kinases, 300 protein phosphatases, and 1500 transcription factors. By contrast, nonprotein messengers are relatively few. They include cyclic nucleotides (Newton et al., 1999), hydrogen ions (Guern et al., 1991), active oxygen species (Van Breusegem et al., 2001), lipids (Ng and Hetherington, 2001; Nurnberger and Scheel, 2001; Munne-Bosch and Alegre, 2002), and, above all, calcium. Changes in cytosolic free calcium ([Ca2+]c) are apparent during the transduction of a very wide variety of abiotic and biotic signals. The spectrum of stimuli that evokes rapid changes in [Ca2+]c has been cataloged in a number of recent reviews (Sanders et al., 1999; Knight, 2000; Anil and Rao, 2001; Knight and Knight, 2001; Rudd and Franklin-Tong, 2001). Abiotic stimuli include light—with red, blue, and UV/B irradiation each acting via different receptors and leading to distinct developmental responses (Shacklock et al., 1992; Baum et al., 1999; Frohnmeyer et al., 1999), low and high temperature, touch, hyperosmotic stress, and oxidative stress. Biotic stimuli include the hormones abscissic acid (ABA) and gibberellin, fungal elicitors, and nodulation (Nod) factors. An all-pervading question during the last decade of calcium signaling research has revolved around the issue of specificity (McAinsh and Hetherington, 1998). How can a simple nonprotein messenger be involved in so many signal transduction pathways and yet still convey stimulus specificity within a variety of pathways? Ostensibly there are a number reasonable nonexclusive answers to this question. First, the Ca2+ signal itself might be a necessary but insufficient trigger for the response, with effective signal transduction occurring only should another signal change in parallel. Second, specificity might be encoded by the spatial properties of the Ca2+ signal, either because the signal is compartmentally localized (for example, to the nucleus, rather than the cytosol) or because the source of the Ca2+ signal (from outside the cell or from intracellular stores) can selectively trigger response elements. Third, the dynamic properties of the Ca2+ signal might determine the efficacy with which the response is elicited. Fourth, of course, the appropriate response elements must be present in the particular cell type in which the Ca2+ signal arises. Since Ca2+ signaling was last reviewed in this journal (Sanders et al., 1999), remarkable advances have been made in addressing this central problem of specificity, in many cases thanks to the insights provided by genetic approaches. Thus, while alluding briefly to the earlier literature, the present review will focus on developments in our understanding that have occurred over the past four years. Decoding Calcium Signals Leads to a Specific Response at the Cellular Level. Various feedback mechanisms from the calcium sensor (or “decoder”) are possible. These could include the regulation of calcium spikes via the control of calcium permeable channel gating (e.g., through EF binding hands, or via Ca2+/CaM binding) or via control of pump activity. Schematic Representation of Major Identified Ca2+ Transport Pathways in Arabidopsis Cell Membranes. Blue circles represent energized transport systems. ACA1, ACA4, ACA8 are autoinhibited calcium ATPases identified at a molecular level. The direction of Ca2+ pumping for ACA1 is hypothetical. ECA is an ER-type calcium ATPase. ACAx in the central vacuole and in the Golgi has not been identified at a molecular level. CAX1 is a Ca2+/H+ antiporter expected to be localized at the vacuolar membrane. Red squares represent Ca2+-permeable channels. At the plasma membrane, nonselective cation (NSC) channels, depolarization activated channels (DACs) and hyperpolarization activated channels (HACs) have been characterized at an electrophysiological but not at a molecular level. A two-pore channel (TPC1) has been shown to complement a yeast mutant deficient in Ca2+ uptake, but channel location is hypothetical. Using electrophysiolocal techniques, cyclic nucleotide gated channels (CNGC1 and CNGC2) were shown to be permeable to calcium. Plasma membrane location is again hypothetical. Glutamate receptors (GLRs) might be involved in the increase of cytosolic calcium concentrations and have been identified at a molecular level. The channels identified at endomembranes have been charac