Journal
PARASITOLOGY
Volume 127, Issue -, Pages 349-356Publisher
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S003118200300386X
Keywords
praziquantel; Ca2+ channel; schistosomiasis; protein kinase C
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Funding
- NIAID NIH HHS [AI 40522, R01 AI040522, N01-AI-55270] Funding Source: Medline
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Praziquantel, the drug of choice against schistosomiasis, disrupts calcium (Ca2+) homeostasis in schistosomes via an unknown mechanism. Voltage-gated Ca2+ channels are heteromultimeric transmembrane protein complexes that contribute to impulse propagation and also regulate intracellular Ca2+ levels. beta subunits modulate the properties of the poreforming alpha(1) subunit of high voltage-activated Ca2+ channels. Unlike other Ca2+ channel beta subunits, which have current stimulatory effects, a beta subunit subtype found in S. mansoni (SmbetaA) and S. japonicum (Sjbeta) dramatically reduces current levels when co-expressed with Ca2+ channel alpha(1) subunits in Xenopus oocytes. It also confers praziquantel sensitivity to the mammalian Ca(v)2.3 alpha(1) subunit. The Beta Interaction Domains (BIDs) of SmbetaA and Sjbeta lack 2 conserved serines that each constitute a consensus site for protein kinase C (PKC) phosphorylation. Here, we use site-directed mutagenesis of schistosome beta subunits to show that these unique functional properties are correlated with the absence of these consensus PKC sites in the BID. Furthermore, a second schistosome beta subunit subtype contains both serines in the BID, enhances currents through alpha(1) subunits, and does not confer praziquantel sensitivity. Thus, phosphorylation sites in the BID may play important roles in defining the modulatory properties and pharmacological sensitivities of schistosome Ca2+ channel subunits.
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