Calcium capacitative entry

Ca2+ can enter cells via voltage- or ligand-dependent channels and by capacitative entry. These three fundamental mechanisms of regulated calcium ion entry across the plasma membrane involve, respectively, voltage-dependent Ca2+ channels, ligand-gated Ca2+ channels and capacitative Ca2+ entry associated with phospholipase C-coupled receptors. 

Capacitative Ca2+ entry is the predominant mode of regulated Ca2+ entry in nonexcitable cells but it also occurs in a number of excitable cell types. This pathway of Ca2+ entry is usually associated with the activation of phospholipase C, which mediates the formation of IP3 (see Ch. 20). Intracellular application of IP3 mimics the ability of hormones and neurotransmitters to activate calcium ion entry, and activation of calcium ion entry by hormones and neurotransmitters can be blocked by intracellular application of low-molecular-weight heparin, which potently antagonizes IP3 binding to its receptor. There is considerable evidence for the presence of an IP3 receptor in the plasma membrane of some cells types. 1(1,3,4,5)P4, a product of IP3 phosphorylation, has been shown in some cells to augment this action of IP3 in activating PM calcium ion entry, but in others IP3 alone is clearly sufficient. 

However, the current view of the regulation of calcium ion entry into the cytoplasm by PLC-linked stimuli holds that activation occurs not as a direct result of the action of IP3 on the plasma membrane but indirectly, as a result of depletion of calcium ions from an intracellular store by IP3 [14]. In the context of this capacitative model , the actions of intracellularly applied IP3 and heparin reflect the effects of these maneuvers on intracellular release process from ER into cytosol, rather than via the plasma membrane. The reported actions of I(1,3,4,5)P4, if in fact they do represent physiological control mechanisms, may reflect an ability of I(1,3,4,5)P4 to augment the calcium-releasing ability of IP3, rather than a distinct and... 

Channels associated with capacitative calcium ion entry have been characterized electrophysiologically. In leukocytes, the current associated with the depletion of intracellular Ca2+ stores is highly Ca2+-selective and, on the basis of noise analysis, is believed to involve minute single channels [16] (see Ch. 6). This is the calcium release-activated calcium current (ICrac)- In other cell types, currents with significantly different properties have been identified, including in some instances store-operated nonse-lective cation channels. These marked electrophysiological distinctions may be indicative of distinct channel types mediating capacitative calcium ion entry in different cell types. 

Now described as a trp superfamily, more than 20 vertebrate trp homologs have been identified and these can be divided phylogenetically into three subfamilies trpC (termed canonical as they are most closely related to Drosophila trp), trpV and trpM. Some of these proteins are potential contenders for the capacitative calcium ion entry channel. In particular, expression of members of the TRPC and TRPV families in mammalian cells has been shown to augment capacitative calcium ion entry, but their role is still a matter for debate [17]. 

The functions of the calcium-storage capacity of the ER are at least threefold the association of Ca2+ with Ca2+-binding proteins in the ER is part of a chaperone function that is essential for normal protein synthesis the rapid rate of Ca2+ uptake by endoplasmic pumps provides shortterm cytoplasmic Ca2+ buffering that resists untoward and transient changes in [Ca2+] and, finally, many signaling pathways employ elevated [Ca2+] to activate physiological processes. Extensive Ca2+ release from ER is coupled to activation of Ca2+ entry across the plasma membrane, a process known as capacitative calcium entry, which is discussed below. 

While the molecular identity of the capacitative Ca2+ entry channel is not known, a candidate is a homolog of the Drosophila mutant trp. This photoreceptor mutant is incapable of maintaining a sustained photoreceptor potential. This phenotype could be mimicked by the calcium entry blocker lanthanum, and it was suggested that the related defect is a failure of Ca2+ entry. 

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Enfissi, A., Prigent, S., Colosetti, P. and Capiod, T., 2004, The blocking of capacitative calcium entry by 2-aminoethyl diphenylborate (2-APB) and carboxyamidotriazole (CAI) inhibits proliferation in Hep G2 and Huh-7 human hepatoma cells. Cell Calcium 36, 459-467. 

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Varadi, A., Cirulli, V. and Rutter, G. A., 2004, Mitochondrial localization as a determinant of capacitative Ca2+ entry in HeLa cells. Cell Calcium 36, 499—508. 

Williams, S. S., French, J. N., Gilbert, M., Rangaswami, A. A., Walleczek, J. and Knox, S. J., 2000, Bcl-2 overexpression results in enhanced capacitative calcium entry and resistance to SKF-96365-induced apoptosis. Cancer lies 60, 4358-61. 

Leissring, M. A., Akbari, Y., Fanger, C. M., Cahalan, M. D., Mattson, M. P., and LaFerla, F. M. (2000). Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 149, 793-798. 

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Huang, H. M., et al., 2005. Selective antioxidants differentially modify endoplasmic reticulum Ca2-I- stores and capacitative calcium entry. Soc Neurosci. 35, 93-100. 

It is noteworthy that the inactivation of the Heliothis RyR at millimolar [Ca ] was prevented at all flubendiamide concentrations tested. This could plausibly explain the insecticidal mechanism since deactivation of calcium release channels at high [Ca ] would be essential to terminate the intracellular calcium transient (27). According to this hypothesis, ryanodine receptors would be fixed in the (sub)conductance conformation leading to calcium store depletion and, possibly, to subsequent activation of capacitative calcium entry through plasma membrane channels. This would override compensatory calcium removal mechanisms such as the sarcoplasmic Ca-ATPase (SERCA) activity and the sodium-calcium exchanger (NCX) in the plasma membrmie. The sustained high intracellular [Ca would finally lead to muscle contraction paralysis that is consistently observed in flubendiamide-affected lepidopteran larvae. 

Narayanan, B. Islam, M. N. Bartelt, D. Ochs, R. S. A direct mass-action mechanism explains capacitative calcium entry in Jurkat and skeletal L6 muscle cells. J. Biol. Chem. 2003,278,44188-44196. 

Lomax, R. B. Herrero, C. J. et al. (1998). "Capacitative Ca2+ entry into Xenopus oocytes is sensitive to omega-conotoxins GVIA, MVIIA and MVIIC." Cell Calcium, 23(4), 229-39. 

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