期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 202, 期 5, 页码 651-662出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20050687
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资金
- NIAID NIH HHS [AI054933, AI40127, R21 AI054933, R01 AI040127] Funding Source: Medline
- NICHD NIH HHS [HD39685] Funding Source: Medline
- NIGMS NIH HHS [R37 GM045374, R01 GM045374, GM45374] Funding Source: Medline
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.
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