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ARTICLE
ESSAYS ON APS CLASSIC PAPERS
Department of Physiology, University of Extremadura, Cáceres, Spain
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ABSTRACT |
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KWAN CY, TAKEMURA H, OBIE JF, THASTRUP O, AND PUTNEY JW JR.: Effects of MeCh, thapsigargin, and La3+ on plasmalemmal and intracellular Ca2+ transport in lacrimal acinar cells. Am J Physiol Cell Physiol 258: C1006–C1015, 1990. (http://ajpcell.physiology.org/cgi/reprint/258/6/C1006)
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The paper by Kwan et al. (6) also raised key conceptual issues concerning the mechanism of Ca2+ influx into agonist-activated cells. Previous observations had suggested that the entry of extracellular Ca2+ involved a process of direct movement of Ca2+ into the intracellular stores, perhaps by a structure analogous to a gap junction and activated when the concentration of free Ca2+ in the stores was reduced (7, 8). This hypothesis limited the role of Ca2+ entry to the refilling of the intracellular Ca2+ pools after or during agonist stimulation. The seminal paper by Kwan et al. provided new information on the pathways for filling agonist-sensitive Ca2+ stores after Ca2+ mobilization in lacrimal cells based on the use of the trivalent cation La3+. The authors were familiar with the studies of C. van Breemen concerning the inhibitory effect of high concentrations of La3+ on the activity of the plasma membrane Ca2+-ATPase (see Ref. 3), a major mechanism for Ca2+ extrusion. In lacrimal acinar cells, La3+ blocked both Ca2+ extrusion and entry. Therefore, they reasoned that by preventing Ca2+ entry and extrusion they could determine whether Ca2+ released into the cytoplasm could replenish the stores, which was the case, providing evidence to the idea that the refilling process did not involve a direct route into the endoplasmic reticulum, but rather resulted from a sequential Ca2+ entry into the cytoplasm and subsequent accumulation in the Ca2+ stores by SERCA pumps (6).
The key conceptual issues reported by Kwan et al. (6) have been extensively cited (according to the Thomson ISI Web of Knowledge index, this article has been referenced 
180 times, 17 citations during the first year after publication, which indicates that the study received immediate support from the scientific community) and are the basis for subsequent scientific studies by researchers from around the world on the mechanisms involved in the activation of capacitative Ca2+ entry.
The mechanism by which the filling state of the intracellular Ca2+ stores regulates Ca2+-permeable channels in the plasma membrane has been a topic of much discussion and debate. Current hypotheses fall into four main categories: indirect coupling, classic conformational coupling, de novo conformational coupling, and secretion-like coupling. The indirect coupling assumes the generation of diffusible molecules that gate capacitative Ca2+ channels. The diffusible messengers include a still uncharacterized calcium-influx factor, cGMP, tyrosine kinases, small GTP-binding proteins, a product of cytochrome P-450, and a Ca2+-calmodulin-dependent step.
The direct (conformational) coupling proposes a physical interaction between capacitative Ca2+ channels in the plasma membrane and IP3 receptors in the membrane of the intracellular Ca2+ stores. Two possibilities have been described for the conformational coupling model. The classic conformational coupling hypothesis suggests that the Ca2+ store must be close enough to the plasma membrane to allow a constitutive protein-protein interaction between capacitative Ca2+ channels and IP3 receptors (1). This hypothesis has been supported by the demonstration that expressed exogenous canonical transient receptor potential (TRPC) channels interact with IP3 receptors under resting conditions and the finding that IP3 receptor sequences can modulate capacitative Ca2+ entry (5).
A modification of the classic conformational coupling, the so-called de novo conformational coupling model, proposes that portions of the Ca2+ stores, containing IP3 receptors, initially distant from the plasma membrane, might be transported to the plasma membrane to facilitate de novo protein coupling. Consistent with this hypothesis, Ca2+ store depletion leads to trafficking of portions of the Ca2+ stores toward the plasma membrane to allow a reversible interaction between IP3 receptors and capacitative Ca2+ channels (10). Supporting this hypothesis, we found coimmunoprecipitation of naturally expressed TRPC1 and the type II IP3 receptor (IP3RII) upon Ca2+ store depletion but not at resting conditions in human platelets (12). The coupling process is regulated by the actin cytoskeleton, which plays a dual role, acting as a negative cortical clamp that prevents constitutive coupling but also providing support for the coupling between IP3 receptors and capacitative Ca2+ channels (10).
The fourth model for the activation of capacitative Ca2+ entry is the secretion-like coupling hypothesis, based on the translocation and insertion of preformed channels into the plasma membrane by vesicle fusion. The idea of vesicle fusion to explain the activation of capacitative Ca2+ entry has received support from studies reporting that cell stimulation with physiological agonists or treatment with thapsigargin increase the expression of stored TRPC channels in the plasma membrane (2, 4).
Recent studies have shown that some of these models for capacitative Ca2+ entry might coexist in a single cell type, such as human platelets (11) or LNCaP human prostate cancer epithelial cells (15), which further support the complexity of the mechanisms involved in the activation capacitative Ca2+ entry in different cellular models.
Alterations in capacitative Ca2+ entry has been shown to be at least partially responsible for a number of pathologies, including acute pancreatitis, type 2 diabetes mellitus, primary immunodeficiency, Alzheimer disease, hypertension, and some types of cancer. The seminal paper of Kwan and coworkers (6) revealed characteristics of capacitative Ca2+ entry of great significance and provided the groundwork on which subsequent studies are based. The understanding of the mechanisms of capacitative Ca2+ entry is a remarkable finding regarding cellular physiology and pathology.
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTREFERENCES |
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2. Bezzerides VJ, Ramsey IS, Kotecha S, Greka A, and Clapham DE. Rapid vesicular translocation and insertion of TRP channels. Nat Cell Biol 6: 709–720, 2004.[CrossRef][ISI][Medline]
3. van Breemen C and De Weer P. Lanthanum inhibition of 45Ca efflux from the squid giant axon. Nature 226:760–761, 1970.[CrossRef][Medline]
4. Cayouette S, Lussier MP, Mathieu EL, Bousquet SM, and Boulay G. Exocytotic insertion of TRPC6 channel into the plasma membrane upon Gq protein-coupled receptor activation. J Biol Chem 279: 7241–7246, 2004.
5. Delmas P, Wanaverbecq N, Abogadie FC, Mustry M, and Brown DA. Signaling microdomains define the specificity of receptor-mediated InsP3 pathways in neurons. Neuron 14: 209–220, 2002.
6. Kwan CY, Takemura H, Obie JF, Thastrup O, and Putney JW Jr. Effects of MeCh, thapsigargin, and La3+ on plasmalemmal and intracellular Ca2+ transport in lacrimal acinar cells. Am J Physiol Cell Physiol 258: C1006–C1015, 1990.
7. Merritt JE and Rink TJ. Regulation of cytosolic free calcium in fura-2-loaded rat parotid acinar cells. J Biol Chem 262: 17362–17369, 1987.
8. Putney JW Jr. A model for receptor-regulated calcium entry. Cell Calcium 7: 1–12, 1986.[CrossRef][ISI][Medline]
9. Putney JW Jr. Pharmacology of capacitative calcium entry. Mol Interv 1: 84–94, 2001.
10. Rosado JA, Jenner S, and Sage SO. A role for the actin cytoskeleton in the initiation and maintenance of store-mediated calcium entry in human platelets. Evidence for conformational coupling. J Biol Chem 275: 7527–7533, 2000.
11. Rosado JA, Lopez JJ, Harper A, Harper MT, Redondo PC, Pariente JA, Sage SO, and Salido GM. Two pathways for store-mediated calcium entry differentially dependent on the actin cytoskeleton in human platelets. J Biol Chem 279: 29231–29235, 2004.
12. Rosado JA and Sage SO. Coupling between inositol 1,4,5-trisphosphate receptors and human transient receptor potential channel 1 when intracellular Ca2+ stores are depleted. Biochem J 350: 631–635, 2000.
13. Takemura H, Hughes AR, Thastrup O, and Putney JW Jr. Activation of calcium entry by the tumor promoter thapsigargin in parotid acinar cells. Evidence that an intracellular calcium pool and not an inositol phosphate regulates calcium fluxes at the plasma membrane. J Biol Chem 264: 12266–12271, 1989.
14. Thastrup O. Role of Ca2+-ATPases in regulation of cellular Ca2+ signalling, as studied with the selective microsomal Ca2+-ATPase inhibitor, thapsigargin. Agents Actions 29: 8–15, 1990.[CrossRef][ISI][Medline]
15. Vanden Abeele F, Lemonnier L, Thebault S, Lepage G, Parys JB, Shuba Y, Skryma R, and Prevarskaya N. Two types of store-operated Ca2+ channels with different activation modes and molecular origin in LNCaP human prostate cancer epithelial cells. J Biol Chem 279: 30326–30337, 2004.
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