A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients.
Engagement of the TCR triggers sustained Ca(2+) entry through Ca(2+) release-activated Ca(2+) (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 Ca(2+) influx and severely impaired T cell activation. The lack of Ca(2+) influx is not due to deficient regulation of Ca(2+) stores or expression of several genes implicated in controlling Ca(2+) 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 Ca(2+) 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.
Feske
Stefan
S
CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Prakriya
Murali
M
Rao
Anjana
A
Lewis
Richard S
RS
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D004594:Electrophysiology; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
D015220:Calcium Channels; D051664:Kv1.3 Potassium Channel; D011948:Receptors, Antigen, T-Cell; D002118:Calcium