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Published 6 September 2005. doi:10.1084/jem.20050687
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 5, 651-662
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ARTICLE

 A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients

Stefan Feske1, Murali Prakriya2, Anjana Rao1, and Richard S. Lewis2

1 CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115
2 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305

CORRESPONDENCE Richard S. Lewis: rslewis{at}stanford.edu

Engagement of the TCR triggers sustained Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, which helps drive gene expression underlying the T cell response to pathogens. The identity and activation mechanism of CRAC channels at a molecular level are unknown. We have analyzed ion channel expression and function in T cells from SCID patients which display 1–2% of the normal level of Ca2+ influx and severely impaired T cell activation. The lack of Ca2+ influx is not due to deficient regulation of Ca2+ stores or expression of several genes implicated in controlling Ca2+ entry in lymphocytes (kcna3/Kv1.3, kcnn4/IKCa1, trpc1, trpc3, trpv6, stim1). Instead, electrophysiologic measurements show that the influx defect is due to a nearly complete absence of functional CRAC channels. The lack of CRAC channel activity is correlated with diminished voltage sensitivity and slowed activation kinetics of the voltage-dependent Kv1.3 channel. These results demonstrate that CRAC channels provide the major, if not sole, pathway for Ca2+ entry activated by the TCR in human T cells. They also offer evidence for a functional link between CRAC and Kv1.3 channels, and establish a model system for molecular genetic studies of the CRAC channel.

Abbreviations used: 2-APB, 2-aminoethyldiphenyl borate; CaV, voltage-gated Ca2+; CRAC, Ca2+ release-activated Ca2+; CTX, charybdotoxin; DVF, divalent-free; ICRAC, CRAC current; MIC, Mg2+-inhibited cation; PLC, phospholipase C; PMCA, plasma-membrane Ca2+-ATPase; ShK toxin, Stichodactyla helianthus toxin; STIM, stromal interaction molecule; TG, thapsigargin; TRP, transient receptor potential.

S. Feske and M. Prakriya contributed equally this work.


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