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Trendsetters
Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y CSIC, Departamento de Fisiología y Bioquímica, Facultad de Medicina, 47005-Valladolid, Spain
Ca2+ release from the intracellular Ca2+ stores on stimulation with physiological agonists is often followed, after a brief lag, by Ca2+ entry from the extracellular medium. This Ca2+ entry is due to activation of store-operated Ca2+ channels (SOC) of the plasma membrane, which open when the intracellular Ca2+ stores empty. On removal of the agonist, the stores refill and Ca2+ entry ceases. This mechanism, originally called capacitative Ca2+ entry (10), reinforces the cytosolic Ca2+ signal and helps to refill the stores once the action of the agonist has elapsed.
Figure 1
illustrates the essential steps and interactions between stores and SOC. The mechanisms for coupling the stores to activation and deactivation of SOC are unknown. Several variants of chemical and conformational coupling have been proposed (for detailed review, see Ref. 8). We have referred recently to SOC in the context of the control of cellular Ca2+ homeostasis (1). In another recent NIPS review, it was proposed that activation could involve translocation of SOC from the stores [the endoplasmic reticulum (ER)] to the plasma membrane by exocytic mechanisms (3). Two exciting papers in the journal Cell provide new insights into these matters (9, 11). Yao et al. (11) find that Ca2+ entry uncouples from store depletion in cell-attached giant membrane patches of Xenopus oocytes but not in the rest of the plasma membrane, suggesting that relative topology of plasma membrane and ER must be preserved for normal activation of SOC. In the same direction, Patterson et al. (9) find that treatment with either jasplakinolide (an actin-polymerizing drug) or calyculin A (a protein-phosphatase inhibitor) uncouples SOC from store depletion in two smooth muscle cell lines. Both drugs produced similar modifications of the actin cytoskeleton, a redistribution that formed a subplasmalemmal F actin layer that displaced ER to a deeper position into the cytoplasm. The actin cytoskeleton disassembly by cytochalasin D did not uncouple SOC; on the contrary, it disrupted the subplasmalemmal actin accumulation effected by calyculin A and reversed the inhibition of SOC by this drug. Thus the findings in both papers suggest that close proximity between ER and plasma membrane, which is disturbed by either gigaseal formation or subplasmalemmal actin accumulation, is required for coupling. This property is reminiscent of what is observed for secretory exocytosis. In addition, Yao et al. (11) find that expression of dominant-negative mutants of SNAP-25 (a exocytic apparatus protein) prevented activation of SOC and that treatment with botulinum neurotoxin A (which cleaves SNAP-25) produced 50% inhibition. Their conclusion is that coupling of the stores to SOC activation takes place by translocation of SOC (or an activator protein) from the ER to the plasma membrane by a secretion-like mechanism.
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In addition, there may be problems with kinetics. The time course of deactivation of SOC on refilling of the Ca2+ stores is quite fast. In human neutrophils stimulated with platelet-activating factor, deactivation does not happen if the stores are not allowed to refill, but half deactivation takes <30 s once they are allowed to refill (Fig. 2A). When store depletion is performed with ionomycin and stores are then refilled to 40% (20 s at 37°C), half deactivation takes ~7 s at 37°C and ~20 s at 25°C (Fig. 2B). With the use of a lipophilic Ca2+ chelator to instantly decrease and increase the Ca2+ concentration inside the stores, Hofer et al. (2) found complete deactivation of SOC by store filling within 14 s in BHK-21 fibroblasts and within 60 s in RBL-1 leukemia cells. It is hard to admit that such a fast decline of Ca2+ entry may happen by endocytosis of SOC. In systems regulated by exo/endocytic mechanisms, such as aquaporins, the vasopressin-sensitive water channels of the kidney (5), or GLUT4, the insulin-sensitive glucose transporter of the adipocytes (4), reversal of the transport activity requires minutes or hours.
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In summary, the new findings on the involvement of secretory machinery on activation of SOC open novel and stimulating perspectives and must be taken into account for future research. However, the exo/endocytic model does not explain adequately the whole activation/deactivation cycle of SOC, nor does it exclude conformational or chemical coupling steps. Most probably, we will have to wait for definitive identification of the SOC channels and the Ca2+-sensing mechanism at the stores before having a final answer.
| This is the last Trendsetter under the editorship of Dr. Heinz Valtin, who will retire effective 1 July 2000. The Officers of APS and IUPS and the NIPS Editorial Staff join together to express their lasting gratitude to Dr. Valtin for his long and loyal service and his outstanding contributions to this journal. Trendsetters will no longer appear in every issue of NIPS.
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Acknowledgments
After submission of this Trendsetter, very interesting comments on these matters have been published by Putney (Cell 99: 5–8, 1999) and by Berridge et al. (Science 287: 1604–1605, 2000).
Footnotes
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.
Heinz Valtin
Editor, TRENDSETTERS
References
| Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only. |
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