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

Stefan Feske, Murali Prakriya, Anjana Rao, Richard S. Lewis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

186 Scopus citations


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. JEM

Original languageEnglish (US)
Pages (from-to)651-662
Number of pages12
JournalJournal of Experimental Medicine
Issue number5
StatePublished - Sep 5 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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