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First published online February 23, 2005
doi: 10.1242/10.1242/jcs.01705

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Another dimension to calcium signaling: a look at extracellular calcium

VA Boston Healthcare System and Brigham & Women's Hospital, Department of Surgery, Harvard Medical School, 1400 VFW Parkway, West Roxbury, MA 02132, USA

View larger version (95K): [in a new window]   Fig. 1. Relationship between intracellular and extracellular [Ca2+] changes in polarized gastric epithelial cells. Intracellular inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3]-sensitive internal stores contain large amounts of Ca2+. Stimulation of cells with an Ins(1,4,5)P3-generating agonist results in the release of Ca2+ into the cytoplasm, and a drop in free intraluminal [Ca2+] in stores of several hundred µM. The resulting Ca2+ spike in the highly buffered cytoplasmic milieu elevates free intracellular [Ca2+] from a resting value of 100 nM to 1000 nM. Much of this Ca2+ is rapidly extruded by Ca2+-export mechanisms, such as the plasma membrane Ca2+-ATPase (PMCA) pump, which has an apical localization in these cells. Extracellular [Ca2+] in the restricted luminal domain of gastric glands transiently increases by hundreds of µM as a consequence of Ca2+ extrusion. Concomitantly, store depletion triggers the opening of store-operated channels (SOCs) in the basolateral plasma membrane and the resulting Ca2+ influx depletes extracellular Ca2+ in the limited interstitial spaces by several hundred µM (Caroppo et al., 2001; Hofer et al., 2004). When Ins(1,4,5)P3 production is terminated, reuptake of Ca2+ into internal stores mediated by the sarco-endoplasmic reticulum ATPase (SERCA) causes Ca2+ entry to cease.

View larger version (53K): [in a new window]   Fig. 2. Signal transduction and CaR. CaR intersects with two classical signaling pathways, working through Gq/G11 to stimulate intracellular PLC/Ins(1,4,5)P3/Ca2+ signaling, and through PTX-sensitive Gi to interrupt cAMP production. In addition, CaR is linked to AA production, and various MAP kinase pathways. Abbreviations: AA, arachidonic acid; AC, adenylate cyclase; cAMP, cyclic AMP; DAG, diacylglycerol; ERK, extracellullar signal-regulated protein kinase; Ins(1,4,5)P3, inositol (1,4,5)-trisphosphate; Ins(1,4,5)P3R, inositol (1,4,5)-trisphosphate receptor; JNK, Jun NH2-terminal kinase; MAP kinase, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; cPLA2, cytosolic phospholipase A2; PI4K, phosphoinositide 4-kinase; PKC, protein kinase C; PLC, phospholipase C; PtdIns(4,5)P2, phoshatidylinositol (4,5)-bisphosphate; PTX, pertussis toxin.

View larger version (117K): [in a new window]   Fig. 3. Extracellular [Ca2+] measured with a near-membrane fluorescent indicator in CaR-expressing HEK 293 cell clusters. The figure shows results of experiments in which cells were initially bathed in a low [Ca2+] solution containing a low concentration of the high-affinity Ca2+ chelator BAPTA (25 µM; a). This allowed detection of extracellular [Ca2+] changes by a high-affinity near-membrane fluorescent Ca2+ indicator, fura-C18. Stimulation of intracellular Ca2+ signaling through CaR using 1 mM spermine (b) results in an increase in the fura-C18 ratio (red pseudocolor) in the diffusion-limited clefts between cells, which is indicative of an increase in extracellular [Ca2+]. Extracellular [Ca2+] is reduced even further in the presence of 1 mM BAPTA (c). (d) Membrane localization of the fluorophore (fluorescence at 340 nm excitation, emission 510 nm). For additional details, see De Luisi and Hofer (De Luisi and Hofer, 2003).

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