A VOLTAGE-OPERABLE CURRENT IS INVOLVED IN CA2-LYMPHOCYTES WHEREAS I-CRAC HAS NO APPARENT ROLE( ENTRY IN HUMAN)

Presently, it is thought that a non-voltage-gated current is responsib le for activation-induced Ca2+ entry in nonelectrically excitable cell s such as lymphocytes. However, it has also been proposed that the pat hway instead involves a second messenger-regulated Ca2+ channel that i s voltage operable, where ''voltage operable'' is defined as an intrin sic property of the channel protein(s) rather than a requirement of no rmal gating. To evaluate the contribution of these currents to activat ion-induced Ca2+ influx, each was examined with respect to its ability to account for Ca2+ influx as reported by Ca2+-sensitive dyes. We ide ntified a set of reagents, nordihydroguaiaretic acid and various calmo dulin inhibitors, that inhibits Ca2+ entry and blocks the voltage-oper able current but leaves the non-voltage-gated current unaltered. Furth ermore, nordihydroguaiaretic acid inhibited Ca2+-dependent proliferati on of mitogen-activated human peripheral blood mononuclear cells or Ju rkat T cells and specifically blocked Ca2+-dependent interleukin 2 pro duction by Jurkat T cells to a degree similar to the immunosuppressant drug cyclosporin A. We also identified compounds, amiloride and Mn2+, that block the non-voltage-gated current but have no effect on either the voltage-operable current or Ca2+ entry. Correspondingly, amilorid e had no effect on Ca2+-dependent proliferation of Jurkat cells. These observations imply that blockade of the non-voltage-gated current doe s not block either Ca2+ entry or Ca2+-dependent lymphocyte proliferati on, whereas blockade of the voltage-operable current does. The data su ggest that the voltage-operable current may be a mediator of activatio n-induced Ca2+ entry in lymphocytes.