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Volume 272, Number 52, Issue of December 26, 1997 pp. 32861-32868

Phosphatidylcholine-specific Phospholipase C Regulates Thapsigargin-induced Calcium Influx in Human Lymphocytes

(Received for publication, July 15, 1997, and in revised form, September 19, 1997)

Jerzy-Roch Nofer , Martin Tepel ^§ , Michael Walter ^¶ , Udo Seedorf ^¶ , Gerd Assmann ^¶ and Walter Zidek ^§

From the  Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfälische Wilhelms-Universität, Münster, ^§ Universitätsklinik Marienhospital der Ruhr-Universität Bochum, D-44625 Herne, and ^¶ Institut für Arteroskleroseforschung an der Universität Münster, Münster D-48129, Federal Republic of Germany

The involvement of phosphatidylcholine-specific phospholipase C (PC-PLC) and D (PC-PLD) in the regulation of the thapsigargin-induced Ca²⁺ increase was investigated. Pretreatment of human lymphocytes with the PC-PLC inhibitors D609 or U73122 enhanced the thapsigargin-induced Ca²⁺ influx. By contrast, no effect was observed in the presence of phospholipase D inhibitor butanol. Addition of exogenous PC-PLC but not PC-PLD to lymphocytes prestimulated with thapsigargin led to a decrease of intracellular Ca²⁺. In addition, thapsigargin was shown to release diacylglycerol (DAG) from cellular phosphatidylcholine pools. The thapsigargin-induced DAG formation was inhibited by U73122 and D609 but not by butanol. Moreover, no formation of the PC-PLD activity marker phosphatidylbutanol was detected. Thapsigargin-induced DAG formation was dependent on the Ca²⁺ entry, as it was abolished in the absence of extracellular Ca²⁺ or in the presence of Ni²⁺. Further investigations demonstrated that the inhibition of the cellular DAG target, protein kinase C (PKC), enhanced thapsigargin-induced Ca²⁺ increase, whereas direct PKC activation had an inhibitory effect. Taken together, our results reveal the involvement of PC-PLC in the regulation of the thapsigargin-induced Ca²⁺ increase and point to the existence of a physiologic feedback mechanism activated by Ca²⁺ influx and acting via consecutive activation of PC-PLC and PKC to limit the rise of intracellular Ca²⁺.

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