A CRAC in the Oscillatory Code?

Science Signaling  02 Jun 2009:
Vol. 2, Issue 73, pp. ec183
DOI: 10.1126/scisignal.273ec183

Oscillations in cytoplasmic Ca2+ concentration provide a ubiquitous signaling mechanism that elicits a wide range of cellular responses, with selective activation of Ca2+-sensitive targets thought to depend on the amplitude and frequency of the oscillation. However, these oscillations depend on Ca2+ flux through channels, and Ca2+ microdomains near permeable channels also enable the selective activation of Ca2+ targets. Thus, Di Capite et al. investigated leukotriene C4 (LTC4)–dependent Ca2+ oscillations in mast cells [in which LTC4 elicits Ca2+ release from intracellular stores and activation of store-operated Ca2+ release–activated Ca2+ (CRAC) channels] to explore the role of localized Ca2+ gradients in the response. Analyses of oscillations in the presence or absence of extracellular Ca2+ with or without the addition of La3+ (which suppresses plasmalemmal Ca2+ extrusion and also blocks CRAC channels) indicated that oscillations did not depend on Ca2+ influx through CRAC channels (although influx sustained the time period over which oscillations occurred). However, Ca2+ influx was required for LTC4-dependent activation of c-fos expression: Ca2+ oscillations of similar amplitude and frequency to those that effectively stimulated an increase in c-fos mRNA abundance when Ca2+ influx took place failed to do so when influx was blocked. The Ca2+ chelator EGTA, which blocked oscillations but binds Ca2+ too slowly to interfere with localized Ca2+ signals near open channels, failed to inhibit LTC4-dependent activation of c-fos expression. In contrast, BAPTA, a chelator that binds Ca2+ rapidly, thereby attenuating even local signals, effectively inhibited LTC4-dependent activation of c-fos. Thus, even in the presence of global oscillations of cytoplasmic Ca2+, influx through CRAC channels—rather than simply enabling the replenishment of depleted stores—can provide a local Ca2+ signal crucial to Ca2+-dependent activation of gene expression.

J. Di Capite, S. W. Ng, A. B. Parekh, Decoding of cytoplasmic Ca2+ oscillations through the spatial signature drives gene expression. Curr. Biol. 19, 853–858 (2009). [PubMed]