AJP - Cell Physiology, Vol 271, Issue 5 C1494-C1503, Copyright © 1996 by American Physiological Society

ARTICLES

A voltage-operable current is involved in Ca2+ entry in human lymphocytes whereas ICRAC has no apparent role

J. J. Densmore, D. M. Haverstick, G. Szabo and L. S. Gray
Department of Pathology, University of Virginia, Charlottesville 22908, USA.

Presently, it is thought that a non-voltage-gated current is responsible for activation-induced Ca2+ entry in nonelectrically excitable cells such as lymphocytes. However, it has also been proposed that the pathway instead involves a second messenger-regulated Ca2+ channel that is voltage operable, where "voltage operable" is defined as an intrinsic property of the channel protein(s) rather than a requirement of normal gating. To evaluate the contribution of these currents to activation-induced Ca2+ influx, each was examined with respect to its ability to account for Ca2+ influx as reported by Ca(2+)-sensitive dyes. We identified a set of reagents, nordihydroguaiaretic acid and various calmodulin inhibitors, that inhibits Ca2+ entry and blocks the voltage-operable current but leaves the non-voltage-gated current unaltered. Further-more, nordihydroguaiaretic acid inhibited Ca(2+)-dependent proliferation of mitogen-activated human peripheral blood mononuclear cells or Jurkat T cells and specifically blocked Ca(2+)-dependent interleukin 2 production 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, amiloride had no effect on Ca(2+)-dependent proliferation of Jurkat cells. These observations imply that blockade of the non-voltage-gated current does not block either Ca2+ entry or Ca(2+)-dependent lymphocyte proliferation, whereas blockade of the voltage-operable current does. The data suggest that the voltage-operable current may be a mediator of activation-induced Ca2+ entry in lymphocytes.

This article has been cited by other articles:

				C. A. Gilchrist, M. Leo, C. G. Line, B. J. Mann, and W. A. Petri Jr. Calcium Modulates Promoter Occupancy by the Entamoeba histolytica Ca2+-binding Transcription Factor URE3-BP J. Biol. Chem., February 7, 2003; 278(7): 4646 - 4653. [Abstract] [Full Text] [PDF]

				A. Zweifach Target-Cell Contact Activates a Highly Selective Capacitative Calcium Entry Pathway in Cytotoxic T Lymphocytes J. Cell Biol., February 7, 2000; 148(3): 603 - 614. [Abstract] [Full Text] [PDF]

				D. M. Haverstick, T. N. Heady, T. L. Macdonald, and L. S. Gray Inhibition of Human Prostate Cancer Proliferation in Vitro and in a Mouse Model by a Compound Synthesized to Block Ca2+ Entry Cancer Res., February 1, 2000; 60(4): 1002 - 1008. [Abstract] [Full Text]

				G. Vazquez, A. R. de Boland, and R. L. Boland 1alpha ,25-Dihydroxy-vitamin-D3-induced Store-operated Ca2+ Influx in Skeletal Muscle Cells. MODULATION BY PHOSPHOLIPASE C, PROTEIN KINASE C, AND TYROSINE KINASES J. Biol. Chem., December 18, 1998; 273(51): 33954 - 33960. [Abstract] [Full Text] [PDF]

				D. M. Haverstick, M. Dicus, M. S. Resnick, J. J. Sando, and L. S. Gray A Role for Protein Kinase Cbeta I in the Regulation of Ca2+ Entry in Jurkat T Cells J. Biol. Chem., June 13, 1997; 272(24): 15426 - 15433. [Abstract] [Full Text] [PDF]