1. Agonist interaction with phospholipase C-linked receptors at the plasma membrane can elicit both Ca2+ and Na+ influxes in lymphocytes. While Ca2+ influx is mediated by Ca2+ release-activated Ca2+ (CRAC) channels, the pathway responsible for Na+ influx is largely unknown. 2. We show that thapsigargin, ionomycin, ADP-ribose and IP3 activated a nonselective cation channel in lymphocytes that had a slightly outwardly rectifying I-V relationship, and a single channel conductance of 23.1 pS. We termed this channel a Ca2+ release-activated nonselective cation (CRANC) channel. 3. On activation in cell-attached configuration, switching to an inside-out configuration abolished CRANC channel activity. 4. Transfection of Jurkat T cells with antisense oligonucleotides for LTRPC2 reduced capacitative Ca2+ entry. 5. These results suggest that CRANC channels are responsible for the Na+ influx as well as a portion of the Ca2+ influx in lymphocytes induced by store depletion, that sustained activation of CRANC channels requires some property of the environment of a cell depleted of its Ca2+ stores; and that LTRPC2 protein is a likely component of the CRANC channel. © 2005 Springer Science+Business Media, Inc.