Schistosome Calcium Channel β Subunits

Abstract

Schistosomes are parasitic flatworms that cause schistosomiasis, a major tropical disease. The current drug of choice against schistosomiasis is praziquantel (PZQ), which has minimal side effects and is potent against all schistosome species. The mode of action of PZQ is unknown, though the drug clearly affects Ca 2؉ channel ␣ 1 subunit results in a striking reduction in current amplitude. In the case of Ca v 2.3, this current reduction can be partially reversed by addition of 100 nM PZQ, which results in a significant increase in current amplitude. Thus, these unusual schistosome ␤ subunits can confer PZQ sensitivity to an otherwise PZQ-insensitive mammalian Ca 2؉ channel, indicating that a possible target for PZQ action is the interaction between ␤ subunits and pore-forming ␣ 1 subunits in schistosomes.

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

“…Diverse studies have focused on the phenomenon (Table 3). Initially, it was hypothesized that PZQ1 affects Ca 2ϩ influx through voltage-operated calcium channels (67)(68)(69)(70)(71)(72)(73). However, in subsequent studies, it was shown that calcium accumulation by itself, as measured in parasites maintained in vitro, may not explain the schistosomicidal activity of PZQ1 (71,72).…”

The N Terminus of a Schistosome β Subunit Regulates Inactivation and Current Density of a Cav2 Channel

“…In contrast, the schistosome cytoplasmic ␤ subunits express robustly in mammalian cells (11) and in Xenopus oocytes (8). The less conventional of the two ␤ subunits has unusual structural and functional properties and appears to be involved in the action of praziquantel (8). In contrast, less data are available for the more conventional schistosome ␤ subunit, which does not appear to play a role in praziquantel action.…”

“…Perhaps ␤ Sm represents one of these mechanisms, working to reduce Ca 2ϩ influx by increasing the rate of Ca v channel inactivation (and decreasing current density). The second, "variant" schistosome ␤ subunit also appears to dampen Ca 2ϩ currents (8). Additionally, it is known that schistosomes express a variety of Ca 2ϩ -buffering proteins.…”

“…It is expected that these channels would express better in helminthic clonal cell lines as these may have some specific factors that are needed for functional expression of these ␣1 subunits; to our knowledge these cells lines are not yet available. In contrast, the schistosome cytoplasmic ␤ subunits express robustly in mammalian cells (11) and in Xenopus oocytes (8). The less conventional of the two ␤ subunits has unusual structural and functional properties and appears to be involved in the action of praziquantel (8).…”

“…The current drug of choice against schistosomiasis is praziquantel, which affects Ca 2ϩ homeostasis in adult worms (6). Adults of Schistosoma mansoni express Ca v 2 and Ca v 1 orthologues as well as two ␤ subunit subtypes (7,8). The modus operandi of the schistosome Ca v channels remains largely unknown primarily due to technical challenges in expressing ␣ 1 subunits and to fast rundown of Ca 2ϩ currents in native preparations (9,10).…”