Elsevier

Cell Calcium

Volume 33, Issues 5–6, May–June 2003, Pages 311-321
Cell Calcium

CRAC channels: activation, permeation, and the search for a molecular identity

https://doi.org/10.1016/S0143-4160(03)00045-9Get rights and content

Abstract

The Ca2+ release-activated Ca2+ (CRAC) channel is a highly Ca2+-selective store-operated channel that is expressed in T lymphocytes, mast cells, and other hematopoietic cells. In T cells, CRAC channels are essential for generating the prolonged intracellular Ca2+ ([Ca2+]i) elevation required for the expression of T-cell activation genes. Here we review recent work addressing CRAC channel regulation, pore properties, and the search for CRAC channel genes. Of the current models for CRAC current (ICRAC) activation, several new studies argue against a conformational coupling mechanism in which IP3 receptors communicate store depletion to CRAC channels through direct physical interaction. The study of CRAC channels has been complicated by the fact that they lose activity in the absence of extracellular Ca2+. Attempts to maintain current size by removing intracellular Mg2+ have been found to unmask Mg2+-inhibited cation (MIC/MagNuM/TRPM7) channels, which have been mistaken in several studies for the CRAC channel. Recent studies under conditions that prevent MIC activation reveal that CRAC channels use high-affinity binding of Ca2+ in the pore to achieve high Ca2+ selectivity but have a surprisingly low conductance for both Ca2+ (∼10 fS) and Na+ (∼0.2 pS). Pore properties provide a unique fingerprint that provides a stringent test for potential CRAC channel genes and suggest models for the ion selectivity mechanism.

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.).

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