CRAC channels: activation, permeation, and the search for a molecular identity
Section snippets
The CRAC channel is a prototypic store-dependent channel
Activation of cell surface receptors can elicit Ca2+ entry through several classes of ion channels, including ligand-gated, second-messenger-operated, and store-operated subtypes. SOCs are most strictly defined as being activatable by a decrease in the lumenal concentration of Ca2+ in stores, independently of receptor stimulation. In T cells and mast cells, CRAC channels are activated by antigen receptor stimulation that triggers Ca2+ release from the ER [4], [5], [6], [7], [8], [9]. While they
Regulation of CRAC channels by store depletion
Despite a great deal of work published over the past 10 years, the nature of the signal that links store depletion to activation of CRAC channels is still unclear. The most well-known hypotheses currently include a diffusible activator that is synthesized and/or released from the ER following store depletion, the insertion of active CRAC channels into the plasma membrane through a vesicle fusion mechanism, and functional coupling between CRAC channels and proteins in the ER membrane. It is fair
Ion selectivity and conductance: a useful yardstick for judging candidate CRAC channel genes
Several genes have been proposed in recent years to encode the CRAC channel, based on imaging or patch-clamp studies of cells induced to overexpress candidate genes. A thorough characterization of the conductive pores of these channels can provide the kind of definitive evidence that is needed to test them as candidates. Fluorescence imaging measurements, in which the only readout is the rate of ion binding by intracellular reporter dyes, as well as electrical measurements of total membrane
Future directions
Thus far, the search for a molecular mechanism for the CRAC channel has consisted primarily of making a guess as to what molecules or genes might be involved, and then through overexpression, knockdown, or pharmacological intervention trying to amass evidence in support of this guess. Heterologous expression studies focused on the TRP family thus far have failed to reveal a gene that can recreate all of the properties of the CRAC channel or even its pore. However, it may be premature to rule
Acknowledgements
The work from the authors’ lab cited in this article was supported by a postdoctoral fellowship from the Irvington Foundation for Immunological Research (to M.P.) and NIH grant GM45374 (to R.S.L.).
References (89)
- et al.
The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency
J. Biol. Chem.
(1994) - et al.
A GTP-dependent step in the activation mechanism of capacitative calcium influx
J. Biol. Chem.
(1993) Capacitative calcium entry revisited
Cell Calcium
(1990)- et al.
Endogenously expressed Trp1 is involved in store-mediated Ca2+ entry by conformational coupling in human platelets
J. Biol. Chem.
(2002) - et al.
Phospholipase C-γ is required for agonist-induced Ca2+ entry
Cell
(2002) - et al.
Relationship between intracellular calcium store depletion and calcium release-activated calcium current in a mast cell line (RBL-1)
J. Biol. Chem.
(1998) - et al.
The store-operated calcium current ICRAC: nonlinear activation by InsP3 and dissociation from calcium release
Cell
(1997) - et al.
Impaired NFAT regulation and its role in a severe combined immunodeficiency
Immunobiology
(2000) Recent developments in non-excitable cell calcium entry
Cell Calcium
(2001)‘Quantal’ Ca2+ release and the control of Ca2+ entry by inositol phosphates—a possible mechanism
FEBS Lett.
(1990)
Store-operated Ca2+ entry: evidence for a secretion-like coupling model
Cell
The N-terminal domain of the IP3 receptor gates store-operated hTrp3 channels
Mol. Cell
Current understanding of mammalian TRP homologues
Cell Calcium
Ca2+ entry mediated by store depletion, S-nitrosylation, and TRP3 channels. Comparison of coupling and function
J. Biol. Chem.
Stable activation of single Ca2+ release-activated Ca2+ channels in divalent cation-free solutions
J. Biol. Chem.
2-Aminoethoxydiphenyl borate reveals heterogeneity in receptor-activated Ca2+ discharge and store-operated Ca2+ influx
Cell Calcium
Role of the phospholipase C-inositol 1,4,5-trisphosphate pathway in calcium release-activated calcium current and capacitative calcium entry
J. Biol. Chem.
Comparison of human TRPC3 channels in receptor-activated and store-operated modes. Differential sensitivity to channel blockers suggests fundamental differences in channel composition
J. Biol. Chem.
Modification of store-operated channel coupling and inositol trisphosphate receptor function by 2-aminoethoxydiphenyl borate in DT40 lymphocytes
J. Biol. Chem.
Store depletion-activated CaT1 currents in rat basophilic leukemia mast cells are inhibited by 2-aminoethoxydiphenyl borate. Evidence for a regulatory component that controls activation of both CaT1 and CRAC (Ca2+ release-activated Ca2+ channel) channels
J. Biol. Chem.
2-Aminoethoxydiphenyl borate inhibits phototransduction and blocks voltage-gated potassium channels in Limulus ventral photoreceptors
Cell Calcium
Gating of store-operated channels by conformational coupling to ryanodine receptors
Mol. Cell
Neuronal Ca2+ signalling takes the local route
Curr. Opin. Neurobiol.
Submicroscopic Ca2+ diffusion mediates inhibitory coupling between individual Ca2+ channels
Neuron
Conductance and permeation of monovalent cations through depletion-activated Ca2+ channels (ICRAC) in Jurkat T cells
Biophys. J.
Plasma membrane Ca2+ release-activated Ca2+ channels with a high selectivity for Ca2+ identified by patch-clamp recording in rat liver cells
Hepatology
Constitutive activity of the light-sensitive channels TRP and TRPL in the Drosophila diacylglycerol kinase mutant, rdgA
Neuron
TRPC1 and TRPC5 form a novel cation channel in mammalian brain
Neuron
Coassembly of TRP and TRPL produces a distinct store-operated conductance
Cell
CaT1 and the calcium release-activated calcium channel manifest distinct pore properties
J. Biol. Chem.
CaT1 contributes to the stores-operated calcium current in Jurkat T-lymphocytes
J. Biol. Chem.
Store depletion and calcium influx
Physiol. Rev.
Store-operated calcium channels
Adv. Sec. Mess Phosphoprot. Res.
Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells
Cell Regul.
Activation of Ca2+ current in Jurkat T cells following the depletion of Ca2+ stores by microsomal Ca2+-ATPase inhibitors
J. Immunol.
Immunoglobulin E receptor-activated calcium conductance in rat mast cells
J. Physiol.
Calcium signaling mechanisms in T lymphocytes
Ann. Rev. Immunol.
Target-cell contact activates a highly selective capacitative calcium entry pathway in cytotoxic T lymphocytes
J. Cell Biol.
Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores
Proc. Natl. Acad. Sci.
Capacitative Ca2+ entry is closely linked to the filling state of internal Ca2+ stores: a study using simultaneous measurements of ICRAC and intraluminal [Ca2+]
J. Cell Biol.
Modulation of Ca2+ entry by polypeptides of the inositol 1,4,5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca2+ entry
Proc. Natl. Acad. Sci.
Functional interaction between InsP3 receptors and store-operated Htrp3 channels
Nature
Activation of calcium entry in human carcinoma A431 cells by store depletion and phospholipase C-dependent mechanisms converge on ICRAC-like calcium channels
Proc. Natl. Acad. Sci.
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2015, Cell CalciumCitation Excerpt :The most potent and immediate form of regulator of Orai1 is by Ca2+ itself. Two modes of regulation of Orai1 by an increase in cytoplasmic Ca2+ have been described and extensively studied; fast Ca2+-dependent inactivation (FCDI), which occurs within milliseconds after channel activation, and slow Ca2+-dependent inactivation (SCDI) that requires several minutes to be completed (reviewed in [85,86]). A stretch of negatively charged residues in STIM1 appears to participate in FCDI of Orai1 [87–89], and a protein interacting with STIM1 named SARAF was shown to be essential for SCDI of Orai1 [90].