Calcium/calmodulin-dependent protein kinase II in Schistosoma: Relation to praziquantel action and resistance

Calcium/calmodulin-dependent protein kinase II (CaMKII) performs diverse essential functions through integrating a range of calcium signals. In Schistosoma, two Calmodulin (CaM) genes are characterized. CaMKII exhibits distinct expression patterns across the developmental stages of the parasite. Its significance lies in sustaining Schistosoma survival and maintaining calcium homeostasis. As it is a calcium sensing protein, its function is closely related to the efficacy of praziquantel, the mainstay drug against schistosomiasis. The relationship between CaMKII and praziquantel involves several potential factors. Praziquantel induces an increased calcium influx into Schistosoma that binds CaM and activates CaMKII, which in turn mitigates the effect of the drug and potentially contributes to praziquantel resistance in several ways. By maintaining calcium homeostasis, CaMKII opposes the surge in calcium influx induced by praziquantel. It modulates voltage-gated calcium channels and reduces calcium influx. It also inhibits ryanodine receptors and inositol triphosphate receptors, thus preventing the release of calcium from the sarcoplasmic/endoplasmic reticulum. CaMKII activates nuclear factor-κB and subsequently activates sarco/endoplasmic reticulum calcium-ATPase (SERCA), which increases calcium uptake into the sarcoplasmic/endoplasmic reticulum and decreases cytosolic calcium. Nuclear factor-κB, activated by CaMKII may lead to up-regulation of P-glycoprotein, which facilitates praziquantel efflux. CaMKII also activates calcineurin that inhibits SERCA. Given its pivotal role in Schistosoma homeostasis and survival, CaMKII emerges as a promising target for novel anthelmintic therapies, and its modulation might enhance the efficacy of praziquantel.