Cell Calcium 40 (2006) 561–574 Calcium microdomains and oxidative stress Sean M. Davidson a,∗ , Michael R. Duchen b a The Hatter Cardiovascular Institute, Royal Free and University College Medical School, London, Department of Medicine, 67 Chenies Mews, London WC1E 6HX, United Kingdom b Department of Physiology and Mitochondrial Biology Group, University College London, London, United Kingdom Received 1 August 2006; accepted 23 August 2006 Available online 17 October 2006 Abstract The phenomenon of calcium microdomains is firmly established in the field of subcellular physiology. These regions of localized, transient calcium increase are exemplified by the spontaneous ‘sparks’ released through the ryanodine receptor in myocytes, but include subplasmalem- mal microdomains, focal calcium oscillations and microdomains enclosed within organelles, such as the endoplasmic reticulum, golgi and mitochondria. Increasing evidence suggests that oxidative stress regulates both the formation and disappearance of microdomains. Calcium release channels and transporters are all modulated by redox state, while several mechanisms that generate oxidative or nitrosative stress are regulated by calcium. Here, we discuss the evidence for the regulation of calcium microdomains by redox state, and, by way of example, demonstrate that the frequency of calcium sparks in cardiomyocytes is increased in response to oxidative stress. We consider the evidence for the existence of analogous microdomains of reactive oxygen and nitrogen species and suggest that the refinement of imaging techniques for these species might lead to similar concepts. The interaction between Ca 2+ microdomains and proteins that modulate their formation results in a complex and dynamic, spatial signaling mechanism, which is likely to be broadly applicable to different cell types, adding new dimensions to the calcium signaling ‘toolkit’. © 2006 Elsevier Ltd. All rights reserved. Keywords: Calcium; Oxidative stress; ROS 1. Introduction Mammalian cells are bathed in interstitial fluid that con- tains greater than 1 mM Ca 2+ . Only by functioning continu- ously are extrusion mechanisms able to counter the inward leak of this calcium, and maintain cytosolic free calcium at ∼100 nM. These include the plasma membrane Ca 2+ ATPase (PMCA) and Na + /Ca 2+ exchangers (NCX). Although the means by which calcium slowly leaks into cells is not under- stood, there are a number of routes by which calcium can enter which are much more well-defined. These include Ca 2+ permeant channels, such as transient receptor potential (TRP) channels (activated by a range of extracellular signals), NMDA gated channels in the CNS and, of course, a wide range of voltage-operated Ca 2+ channels (VOC), which ini- tiate the calcium waves that initiate contraction in cardiomy- ∗ Corresponding author. Tel.: +44 207 380 9683. E-mail address: s.davidson@ucl.ac.uk (S.M. Davidson). ocytes [1,2]. Any sudden influx of Ca 2+ through a small local- ized pathway via these mechanisms must inevitably lead to a local, transient increase in [Ca 2+ ] c beneath the plasmalemma. The high calcium buffering capacity of the cytosol limits cal- cium diffusion [3], and so such increases may remain spatially restricted, requiring other mechanisms for amplification and propagation. Such localized increases in [Ca 2+ ] c have been referred to as “Ca 2+ microdomains” (for reviews, see [2], and other articles in this issue of Cell Calcium). However, a discussion of calcium microdomains is not limited to the transient increases that occur beneath the plasma membrane. Both the ER and golgi are microenviron- ments within the cell which contain a concentration of Ca 2+ which is far higher than that within in the cytosol, and so any release of Ca 2+ from these organelles must necessarily also result in a localized increase in [Ca 2+ ] c . Such increases have been defined operationally as “Ca 2+ puffs” (originating from IP3R in the ER) [4], “Ca 2+ sparks” (originating from RyR in the SR) [5], “Ca 2+ marks” (transient increases in mitochon- 0143-4160/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ceca.2006.08.017