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Investigating the effects of nicergoline on calcium signalling in human platelets and megakaryocytes

Investigating the effects of nicergoline on calcium signalling in human platelets and megakaryocytes Thumbnail


Abstract

Recent study suggested that the anti-platelet effect of nicergoline is caused by inhibiting agonist-evoked Ca2+ signalling by disrupting the normal localization of the dense tubular system in human platelets. This effect is brought about by the disruption of the cortical microtubule bundle which plays a role in holding the dense tubular system in its normal location. However, these previous studies did not define the mechanism by which nicergoline induces this disruption of the cortical microtubule bundle. In this study we aimed to further elucidate the mechanism by which nicergoline could disrupt the localization of the microtubules in human platelets. To do this we have examined the effect of inhibitors of microtubule motor proteins such as kinesin, dyneins and myosin, as well as inhibitors of microtubule deacetylases to see whether these can mimic or modulate the effects of nicergoline on platelet Ca2+ signalling and functional responses. These experiments have demonstrated that myosin, dyneins and histone deacetylases are not the targets of nicergoline due to inhibitors of these targets failing to recreate the effects of nicergoline in both Ca2+ signalling and platelet function assays. In contrast, our data does demonstrate the potential for kinesins to be a target of nicergoline’s action, as an inhibitor of these motor proteins recapitulates the effect of this drug on thrombin-evoked Ca2+ signalling and platelet function assays. In addition, combined treatment with both drugs does not produce cumulative effects suggesting that they are working through the same pathway. These data give further insight towards the mechanism underling the anti-platelet effect of nicergoline and suggest an important role for the platelet molecular motor proteins in regulating platelet function and to be a possible target of action for a novel anti-platelet therapy in future.

Publication Date Oct 1, 2017

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